Txnip-trx complex inhibitors and methods of using the same

ABSTRACT

Disclosed herein, inter alia, are compounds and methods for inhibiting the thioredoxin-thioredoxin-interacting-protein (TXNIP-TRX) complex.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/730,988, filed Sep. 13, 2018, which is incorporated herein byreference in its entirety and for all purposes.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

This invention was made with government support under grant no. DP3DK106917-01 awarded by the National Institutes of Health. The governmenthas certain rights in the invention.

REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAMLISTING APPENDIX SUBMITTED AS AN ASCII FILE

The Sequence Listing written in file048440-711001US_Sequence_Listing_ST25.txt, created Aug. 26, 2019, 4,837bytes, machine format IBM-PC, MS Windows operating system, is herebyincorporated by reference.

BACKGROUND

The thioredoxin system, which includes the thioredoxin (TRX) protein,nicotinamide adenine dinucleotide phosphate (NADPH), and thioredoxinreductase (TXNRD1), is a major anti-oxidant system involved in themaintenance of cellular physiology and survival. Dysregulation in thissystem has been associated with metabolic and cardiovascular disorders.Thioredoxin-interacting protein (TXNIP) is an inhibitor of the redoxregulator thioredoxin (TRX), an antioxidant. Increased TXNIP expressionincreases oxidant stress and is associated with diabetes as well asseveral diabetic complications, including diabetic retinopathy, diabeticnephropathy, diabetic neuropathy and cardiovascular disease. InhibitingTXNIP levels chronically may cause unwanted side effects due to themultiple roles of TXNIP in cells. Identifying modulators of theTXNIP-TRX complex formation remains a challenge. Disclosed herein, interalia, are solutions to these and other problems in the art.

BRIEF SUMMARY

In an aspect is provided a compound (e.g., a TXNIP-TRX complexinhibitor) having the formula:

W¹ is —CR¹═, —N═, or —CH═. W² is —CR²═, —N═, or —CH═. R¹ isindependently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —OCX¹ ₃, —OCH₂X¹, —OCHX¹₂, substituted or unsubstituted alkyl, or substituted or unsubstitutedheteroalkyl. R² is independently halogen, —CX² ₃, —CHX² ₂, —CH₂X², —OCX²₃, —OCH₂X², —OCHX² ₂, substituted or unsubstituted alkyl, or substitutedor unsubstituted heteroalkyl. L³ is a bond, —N(R³)—, —C(O)—,—C(O)N(R³)—, —N(R³)C(O)—, —N(H)—, —C(O)N(H)—, —N(H)C(O)—, —C(O)O—,substituted or unsubstituted alkylene, or substituted or unsubstitutedheteroalkylene. R³ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃,—CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl. R⁶ isindependently hydrogen, halogen, —CX⁶ ₃, —CHX⁶ ₂, —CH₂X⁶, —OCX⁶ ₃,—OCH₂X⁶, —OCHX⁶ ₂, —CN, —SR^(6D), —SOR^(6D), —SO₂R^(6D)—SO₃R^(6D),—SO₄R^(6D), —SONR^(6A)R^(6B), —SO₂NR^(6A)R^(6B),—NR^(6C)C(O)NR^(6A)R^(6B), —N(O), —N(O)₂, —NR^(6A)R^(6B), —C(O)R^(6C),—C(O)—OR^(6C), —C(O)NR^(6A)R^(6B), —OR^(6D), —NR^(6A)SO₂R^(6D),—NR^(6A)C(O)R^(6C), —NR^(6A)C(O)OR^(6C), —NR^(6A)OR^(6C),—NR^(6C)NR^(6A)R^(6B), —C(O)NR^(6C)NR^(6A)R^(6B), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl. R^(6A)R^(6B), R^(6C), and R^(6D) are eachindependently hydrogen, oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl. X¹, X²,and X⁶ are independently —F, —Cl, —Br, or —I.

In an aspect is provided a pharmaceutical composition including acompound described herein, or pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable excipient.

In an aspect is provided a method of treating a TXNIP-TRXcomplex-associated disease, the method including administering to asubject in need thereof an effective amount of a TXNIP-TRX complexinhibitor.

In an aspect is provided a method of treating a TXNIP-TRXcomplex-associated disease, the method including administering to asubject in need thereof an effective amount of a TXNIP-TRX complexinhibitor, wherein the TXNIP-TRX complex inhibitor is a compound asdescribed herein, including embodiments. In embodiments, the compoundhas the formula:

wherein W¹, W², L³, and R⁶ are as described herein.

In an aspect is provided a method of treating a metabolic disorder,cardiovascular disease, or inflammatory disease, the method includingadministering to a subject in need thereof an effective amount of acompound, or pharmaceutically acceptable salt thereof, as describedherein, including embodiments. In embodiments, the compound has theformula:

wherein W¹, W², L³, and R⁶ are as described herein.

In an aspect is provided a method of reducing the level of expression ofTXNIP in a cell, the method including contacting the cell with acompound, or pharmaceutically acceptable salt thereof, as describedherein.

In an aspect is provided a method of reducing the level of expression ofTXNIP, the method including contacting TXNIP with a compound, or apharmaceutically acceptable salt thereof, as described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1B. FIG. 1A: TXNIP-TRX complex showing the predicted druggableallosteric sites for small molecules; FIG. 1B: Computational smallmolecule screening strategy. The binding sites predicted using thecomputational method Allosteer.

FIGS. 2A-2D. FIG. 2A. Compound 1 (C1); FIG. 2B. Additional examples ofC1 analogs; FIG. 2C. Examples of substitutions at R¹ and R² (of thescaffold described in FIGS. 2A-2D); FIG. 2D. Examples of moieties.

FIG. 3. Schematic TXNIP-TRX complex showing the predicted allostericsites for small molecule design. The communication pipelines connectingthe TRX site to the allosteric sites were calculated from multiple MD(molecular dynamics) simulations of TXNIP-TRX complex (computational).

FIGS. 4A-4B. Co-IP with anti-TRX in THP 1 cells treated with compoundsunder high glucose condition. THP1 cells were treated by 10 uM compoundsover night, then glucose was added up to 25 mM. The cells were culturedfor 72-96 h. Cell extracts were prepared using cell extract buffer(Thermo Fisher Scientific) and Co-IP were performed with mouse anti-TRX(abcam).

FIG. 5. Co-IP with anti-TRX in THP 1 cells treated with compound 1 underhigh glucose. A: HG no compound 1; B: HG, 3 uM compound 1; C: HG, 6 uMcompound 1; D: HG, 12 uM compound 1; E: HG, 24 uM compound 1.

FIGS. 6A-6B. DARTS Assay results. See Example 2 for additional details.

FIG. 7. C1 blocks High glucose (HG induced) TXNIP-TRX complex formation.We use nondenaturing gel to detect TXNIP-s-s-TRX complex. Under HGcondition, we are able to detect the TXNIP-s-s-TRX complex AddingCompound 1 reduced the detected signal.

FIG. 8. Compound 1 reduces HG-induced expression of TNF (an inflammatorymolecule) in monocytes. High glucose induced TNF expression in THP1cells. This HG induced TNF increase is alleviated by C1 in dose mannner(1.25, 2.5 and 5 uM). Results shown are means±SE of triplet real-timePCRs. *:P=0.002 vs. HG only, by t tests; **:P=0.001 vs. HG only, by ttests.

FIGS. 9A-9B. FIG. 9A. C1 inhibits TXNIP mRNA expression in THP1 cells.THP1 cells were cultured in 25 mM glucose with the indicatedconcentrations of C1 for 72 h. Cell were collected for total RNApreparation. RT-PCR were performed and data shown are the mean+SEM fromtriplicates. Statistical analysis was performed using one-way ANOVA,*<0.0001. FIG. 9B. C1 inhibits TNF-α mRNA expression in THP1 cells. THP1cells were cultured in 25 mM glucose and C1 (uM) as indicated for 72hours and collected for total RNA preparation. RT-PCR was performed.Data shown are the mean+SEM from triplicates. Statistical analysis wasperformed using one-way ANOVA: *<0.02; **<0.0001.

FIGS. 10A-10B. FIG. 10A. C1 inhibits TXNIP mRNA expression in murine RAWmacrophages. RAW cells were cultured in 25 mM glucose with C1 (uM) for72 h. Total RNA was prepared. RT-PCR was performed. Data shown are themean+SEM from triplicates. Statistical analysis was performed for eachcolumn vs. high glucose (HG) DMSO using one-way ANOVA: *<0.0001. FIG.10B. Treatment with C1 decreased TNF-α mRNA expression in murine RAWmacrophages. RAW cells were cultured in 25 mM glucose with C1 (uM) for72 hours. Total RNA was prepared. RT-PCR was performed. Data shown arethe mean+SEM from triplicates. Statistical analysis was performed foreach column vs. HG DMSO using one-way ANOVA: *<0.0001.

FIG. 11. Treatment of murine MIN6 cells with C1 decreased TXNIP but notTNF-α mRNA levels. MIN6 cells were cultured in 25 mM glucose with C1 atuM concentrations for 72 h. Total RNA was prepared. RT-PCR wasperformed. Data shown are the mean+SEM from triplicates. Statisticalanalysis was performed for each column vs. HG DMSO using one-way ANOVA:*<0.0001.

FIG. 12. C1 affects TXNIP and TNF-α mRNA expression in human pancreas1.1B4 β cells. Human 1.1B4 β cells were cultured in 25 mM glucose withC1 (uM) for 72 h. Total RNA was prepared. RT-PCR was performed. Datashown are the mean+SEM from triplicates. Statistical analysis wasperformed for each column vs. HG DMSO using one-way ANOVA: *<0.0001.

FIG. 13. C1 analogs affects TXNIP mRNA expression in THP1 cells. THP1cells were cultured in 25 mM glucose with 5 uM of compounds for 72 h.Total RNA was collected and RT-PCR was performed in triplicate and datashown are the mean+SEM. Statistical analysis was performed using one-wayANOVA: *<0.0001.

FIG. 14. Inhibition of TXNIP-TRX interaction by THP1 cells were culturedin 25 mM glucose with 5 uM C1 for 16-72 h. Aliquots were taken atindicated time points and nuclear cell extracts prepared. Standard co-IPwas performed with mouse anti-TRX antibody overnight. Beads were washedwith buffer and blots treated with rabbit anti-TXNIP antibody.

FIG. 15. C1 stabilizes TXNIP by binding to it in DARTS assay. THP1 cellwere cultured in RPMI 1640 medium in 25 mM glucose for 72 hours. Cellextracts were prepared. C1 was added at the indicated concentrations andprotease was added except in control cells. Aliquots were withdrawn at10, 20, 30 and 40 minutes and loaded onto 10% SDS gels. C1: compound 1;control: without protease.

FIG. 16. C1 protects purified TXNIP from proteolysis in a DARTS assay.Purified TRX and TXNIP proteins and C1 (at the indicated concentrations)were mixed together. Protease was added. Aliquots were withdrawn at 7minutes and loaded on 10% SDS gels. C1: compound 1; control: withoutprotease.

FIG. 17. Hierarchical Clustering using differential expressed genes.Differential expression was calculated using these counts with edgeR (5,6) version 3.0. After correcting for differences in library sizes, afold change of >1.5 and a p-value of <0.05 were applied to selectexpressed genes. The corrected measures of the latter were furtherprocessed using Cluster3.0 (7) to generate a heatmap using JavaTreeView. C=HG treated THP-1 cells (A, B are replicates); T=HG+C1 SuM(C, D are replicates). From top to bottom: FLNA, MPEG1, TKTL1, NATD1,TXNIP, KLF10, KLF2, CD52, TNF, ARRDC4, JMJ1C-AS1, RGMA, EGR1, NPIPA1,GOS2, EPHB1, VSIG4, CFP, CAPS, GLUD1P3, PCDHB14, CCDC153, FAM229A,SMURF2, PDE9A, SLC44A2, ARHGEF25, APBB1, GTF2IRD1, LOC100506688, PPM1K,SLC16A2, PCGF2, HK2, TSPAN2, S1PR5, EFCAB7, MACROD1, GBP5, KIAA1147,ADGRE4P, UQCRHL, DICER1-AS1, PDIA3P1.

FIG. 18. C1 targets TXNIP mRNA in human pancreatic islets. Humanpancreatic islets (500 IEQ) were cultured with PIM(R) (Prodo Labs) in 25mM glucose with C1 as indicated for 48 h. Total RNA was collected.RT-PCR was performed in triplicate and data shown are the mean+SEM.Statistical analysis was performed using one-way ANOVA: *<0.0001.

FIG. 19. Computational screening strategy.

DETAILED DESCRIPTION I. Definitions

The abbreviations used herein have their conventional meaning within thechemical and biological arts. The chemical structures and formulae setforth herein are constructed according to the standard rules of chemicalvalency known in the chemical arts.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight (i.e., unbranched) or branchedcarbon chain (or carbon), or combination thereof, which may be fullysaturated, mono- or polyunsaturated and can include mono-, di- andmultivalent radicals. The alkyl may include a designated number ofcarbons (e.g., C₁-C₁₀ means one to ten carbons). Alkyl is an uncyclizedchain. An alkoxy is an alkyl attached to the remainder of the moleculevia an oxygen linker (—O—). An alkyl moiety may be an alkenyl moiety. Analkyl moiety may be an alkynyl moiety. An alkyl moiety may be fullysaturated. An alkenyl may include more than one double bond and/or oneor more triple bonds in addition to the one or more double bonds. Analkynyl may include more than one triple bond and/or one or more doublebonds in addition to the one or more triple bonds.

The term “alkylene,” by itself or as part of another substituent, means,unless otherwise stated, a divalent radical derived from an alkyl, asexemplified, but not limited by, —CH₂CH₂CH₂CH₂—. Typically, an alkyl (oralkylene) group will have from 1 to 24 carbon atoms, with those groupshaving 10 or fewer carbon atoms being preferred herein. A “lower alkyl”or “lower alkylene” is a shorter chain alkyl or alkylene group,generally having eight or fewer carbon atoms. The term “alkenylene,” byitself or as part of another substituent, means, unless otherwisestated, a divalent radical derived from an alkene.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcombinations thereof, including at least one carbon atom and at leastone heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen andsulfur atoms may optionally be oxidized, and the nitrogen heteroatom mayoptionally be quaternized. The heteroatom(s) (e.g., O, N, S, Si, or P)may be placed at any interior position of the heteroalkyl group or atthe position at which the alkyl group is attached to the remainder ofthe molecule. Heteroalkyl is an uncyclized chain. Up to two or threeheteroatoms may be consecutive, such as, for example, —CH₂—NH—OCH₃ and—CH₂—O—Si(CH₃)₃. A heteroalkyl moiety may include one heteroatom (e.g.,O, N, S, Si, or P). A heteroalkyl moiety may include two optionallydifferent heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moietymay include three optionally different heteroatoms (e.g., O, N, S, Si,or P). A heteroalkyl moiety may include four optionally differentheteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may includefive optionally different heteroatoms (e.g., O, N, S, Si, or P). Aheteroalkyl moiety may include up to 8 optionally different heteroatoms(e.g., O, N, S, Si, or P). The term “heteroalkenyl,” by itself or incombination with another term, means, unless otherwise stated, aheteroalkyl including at least one double bond. A heteroalkenyl mayoptionally include more than one double bond and/or one or more triplebonds in additional to the one or more double bonds. The term“heteroalkynyl,” by itself or in combination with another term, means,unless otherwise stated, a heteroalkyl including at least one triplebond. A heteroalkynyl may optionally include more than one triple bondand/or one or more double bonds in additional to the one or more triplebonds.

Similarly, the term “heteroalkylene,” by itself or as part of anothersubstituent, means, unless otherwise stated, a divalent radical derivedfrom heteroalkyl, as exemplified, but not limited by, —CH₂—CH₂,—S—CH₂—CH₂— and —CH₂, —S—CH₂—CH₂—NH—CH₂—. For heteroalkylene groups,heteroatoms can also occupy either or both of the chain termini (e.g.,alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and thelike). Still further, for alkylene and heteroalkylene linking groups, noorientation of the linking group is implied by the direction in whichthe formula of the linking group is written. For example, the formula—C(O)₂R′— represents both —C(O)₂R′— and —R′C(O)₂—. As described above,heteroalkyl groups, as used herein, include those groups that areattached to the remainder of the molecule through a heteroatom, such as—C(O)R′, —C(O)NR′, —NR′R″, —OR′, —SR′, and/or —SO₂R′. Where“heteroalkyl” is recited, followed by recitations of specificheteroalkyl groups, such as —NR′R″ or the like, it will be understoodthat the terms heteroalkyl and —NR′R″ are not redundant or mutuallyexclusive. Rather, the specific heteroalkyl groups are recited to addclarity. Thus, the term “heteroalkyl” should not be interpreted hereinas excluding specific heteroalkyl groups, such as —NR′R″ or the like.

The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or incombination with other terms, mean, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl,” respectively. Cycloalkyl andheterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, aheteroatom can occupy the position at which the heterocycle is attachedto the remainder of the molecule. A “cycloalkylene” and a“heterocycloalkylene,” alone or as part of another substituent, means adivalent radical derived from a cycloalkyl and heterocycloalkyl,respectively.

In embodiments, the term “cycloalkyl” means a monocyclic, bicyclic, or amulticyclic cycloalkyl ring system. In embodiments, monocyclic ringsystems are cyclic hydrocarbon groups containing from 3 to 8 carbonatoms, where such groups can be saturated or unsaturated, but notaromatic. In embodiments, cycloalkyl groups are fully saturated.Bicyclic cycloalkyl ring systems are bridged monocyclic rings or fusedbicyclic rings. In embodiments, bridged monocyclic rings contain amonocyclic cycloalkyl ring where two non adjacent carbon atoms of themonocyclic ring are linked by an alkylene bridge of between one andthree additional carbon atoms (i.e., a bridging group of the form(CH₂)_(w), where w is 1, 2, or 3). Representative examples of bicyclicring systems include, but are not limited to, bicyclo[3.1.1]heptane,bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane,bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. In embodiments, fusedbicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ringfused to either a phenyl, a monocyclic cycloalkyl, a monocycliccycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. Inembodiments, the bridged or fused bicyclic cycloalkyl is attached to theparent molecular moiety through any carbon atom contained within themonocyclic cycloalkyl ring. In embodiments, cycloalkyl groups areoptionally substituted with one or two groups which are independentlyoxo or thia. In embodiments, the fused bicyclic cycloalkyl is a 5 or 6membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocycliccycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl isoptionally substituted by one or two groups which are independently oxoor thia. In embodiments, multicyclic cycloalkyl ring systems are amonocyclic cycloalkyl ring (base ring) fused to either (i) one ringsystem selected from the group consisting of a bicyclic aryl, a bicyclicheteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and abicyclic heterocyclyl; or (ii) two other ring systems independentlyselected from the group consisting of a phenyl, a bicyclic aryl, amonocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl,a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclicheterocyclyl. In embodiments, the multicyclic cycloalkyl is attached tothe parent molecular moiety through any carbon atom contained within thebase ring. In embodiments, multicyclic cycloalkyl ring systems are amonocyclic cycloalkyl ring (base ring) fused to either (i) one ringsystem selected from the group consisting of a bicyclic aryl, a bicyclicheteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and abicyclic heterocyclyl; or (ii) two other ring systems independentlyselected from the group consisting of a phenyl, a monocyclic heteroaryl,a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclicheterocyclyl. Examples of multicyclic cycloalkyl groups include, but arenot limited to tetradecahydrophenanthrenyl, perhydrophenothiazin-1-yl,and perhydrophenoxazin-1-yl.

In embodiments, a cycloalkyl is a cycloalkenyl. The term “cycloalkenyl”is used in accordance with its plain ordinary meaning. In embodiments, acycloalkenyl is a monocyclic, bicyclic, or a multicyclic cycloalkenylring system. In embodiments, monocyclic cycloalkenyl ring systems arecyclic hydrocarbon groups containing from 3 to 8 carbon atoms, wheresuch groups are unsaturated (i.e., containing at least one annularcarbon carbon double bond), but not aromatic. Examples of monocycliccycloalkenyl ring systems include cyclopentenyl and cyclohexenyl. Inembodiments, bicyclic cycloalkenyl rings are bridged monocyclic rings ora fused bicyclic rings. In embodiments, bridged monocyclic rings containa monocyclic cycloalkenyl ring where two non adjacent carbon atoms ofthe monocyclic ring are linked by an alkylene bridge of between one andthree additional carbon atoms (i.e., a bridging group of the form(CH₂)_(w), where w is 1, 2, or 3). Representative examples of bicycliccycloalkenyls include, but are not limited to, norbornenyl andbicyclo[2.2.2]oct 2 enyl. In embodiments, fused bicyclic cycloalkenylring systems contain a monocyclic cycloalkenyl ring fused to either aphenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclicheterocyclyl, or a monocyclic heteroaryl. In embodiments, the bridged orfused bicyclic cycloalkenyl is attached to the parent molecular moietythrough any carbon atom contained within the monocyclic cycloalkenylring. In embodiments, cycloalkenyl groups are optionally substitutedwith one or two groups which are independently oxo or thia. Inembodiments, multicyclic cycloalkenyl rings contain a monocycliccycloalkenyl ring (base ring) fused to either (i) one ring systemselected from the group consisting of a bicyclic aryl, a bicyclicheteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and abicyclic heterocyclyl; or (ii) two ring systems independently selectedfrom the group consisting of a phenyl, a bicyclic aryl, a monocyclic orbicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclicor bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl. Inembodiments, the multicyclic cycloalkenyl is attached to the parentmolecular moiety through any carbon atom contained within the base ring.In embodiments, multicyclic cycloalkenyl rings contain a monocycliccycloalkenyl ring (base ring) fused to either (i) one ring systemselected from the group consisting of a bicyclic aryl, a bicyclicheteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and abicyclic heterocyclyl; or (ii) two ring systems independently selectedfrom the group consisting of a phenyl, a monocyclic heteroaryl, amonocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclicheterocyclyl.

In embodiments, a heterocycloalkyl is a heterocyclyl. The term“heterocyclyl” as used herein, means a monocyclic, bicyclic, ormulticyclic heterocycle. The heterocyclyl monocyclic heterocycle is a 3,4, 5, 6 or 7 membered ring containing at least one heteroatomindependently selected from the group consisting of O, N, and S wherethe ring is saturated or unsaturated, but not aromatic. The 3 or 4membered ring contains 1 heteroatom selected from the group consistingof O, N and S. The 5 membered ring can contain zero or one double bondand one, two or three heteroatoms selected from the group consisting ofO, N and S. The 6 or 7 membered ring contains zero, one or two doublebonds and one, two or three heteroatoms selected from the groupconsisting of O, N and S. The heterocyclyl monocyclic heterocycle isconnected to the parent molecular moiety through any carbon atom or anynitrogen atom contained within the heterocyclyl monocyclic heterocycle.Representative examples of heterocyclyl monocyclic heterocycles include,but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl,1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl,imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl,isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl,oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl,pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl,thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl(thiomorpholine sulfone), thiopyranyl, and trithianyl. The heterocyclylbicyclic heterocycle is a monocyclic heterocycle fused to either aphenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclicheterocycle, or a monocyclic heteroaryl. The heterocyclyl bicyclicheterocycle is connected to the parent molecular moiety through anycarbon atom or any nitrogen atom contained within the monocyclicheterocycle portion of the bicyclic ring system. Representative examplesof bicyclic heterocyclyls include, but are not limited to,2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-1-yl,indolin-2-yl, indolin-3-yl, 2,3-dihydrobenzothien-2-yl,decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H-indolyl, andoctahydrobenzofuranyl. In embodiments, heterocyclyl groups areoptionally substituted with one or two groups which are independentlyoxo or thia. In certain embodiments, the bicyclic heterocyclyl is a 5 or6 membered monocyclic heterocyclyl ring fused to a phenyl ring, a 5 or 6membered monocyclic cycloalkyl, a 5 or 6 membered monocycliccycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6membered monocyclic heteroaryl, wherein the bicyclic heterocyclyl isoptionally substituted by one or two groups which are independently oxoor thia. Multicyclic heterocyclyl ring systems are a monocyclicheterocyclyl ring (base ring) fused to either (i) one ring systemselected from the group consisting of a bicyclic aryl, a bicyclicheteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and abicyclic heterocyclyl; or (ii) two other ring systems independentlyselected from the group consisting of a phenyl, a bicyclic aryl, amonocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl,a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclicheterocyclyl. The multicyclic heterocyclyl is attached to the parentmolecular moiety through any carbon atom or nitrogen atom containedwithin the base ring. In embodiments, multicyclic heterocyclyl ringsystems are a monocyclic heterocyclyl ring (base ring) fused to either(i) one ring system selected from the group consisting of a bicyclicaryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicycliccycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ringsystems independently selected from the group consisting of a phenyl, amonocyclic heteroaryl, a monocyclic cycloalkyl, a monocycliccycloalkenyl, and a monocyclic heterocyclyl. Examples of multicyclicheterocyclyl groups include, but are not limited to10H-phenothiazin-10-yl, 9,10-dihydroacridin-9-yl,9,10-dihydroacridin-10-yl, 10H-phenoxazin-10-yl,10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl,1,2,3,4-tetrahydropyrido[4,3-g]isoquinolin-2-yl,12H-benzo[b]phenoxazin-12-yl, and dodecahydro-1H-carbazol-9-yl.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” includes, but is not limited to, fluoromethyl,difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl,3-bromopropyl, and the like.

The term “acyl” means, unless otherwise stated, —C(O)R where R is asubstituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, hydrocarbon substituent, which can be a single ring ormultiple rings (preferably from 1 to 3 rings) that are fused together(i.e., a fused ring aryl) or linked covalently. A fused ring aryl refersto multiple rings fused together wherein at least one of the fused ringsis an aryl ring. The term “heteroaryl” refers to aryl groups (or rings)that contain at least one heteroatom such as N, O, or S, wherein thenitrogen and sulfur atoms are optionally oxidized, and the nitrogenatom(s) are optionally quaternized. Thus, the term “heteroaryl” includesfused ring heteroaryl groups (i.e., multiple rings fused togetherwherein at least one of the fused rings is a heteroaromatic ring). A5,6-fused ring heteroarylene refers to two rings fused together, whereinone ring has 5 members and the other ring has 6 members, and wherein atleast one ring is a heteroaryl ring. Likewise, a 6,6-fused ringheteroarylene refers to two rings fused together, wherein one ring has 6members and the other ring has 6 members, and wherein at least one ringis a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to tworings fused together, wherein one ring has 6 members and the other ringhas 5 members, and wherein at least one ring is a heteroaryl ring. Aheteroaryl group can be attached to the remainder of the moleculethrough a carbon or heteroatom. Non-limiting examples of aryl andheteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl,pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl,oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl,benzothiazolyl, benzoxazoyl benzimidazolyl, benzofuran, isobenzofuranyl,indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl,quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl,3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl,2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl,5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl,3-quinolyl, and 6-quinolyl. Substituents for each of the above notedaryl and heteroaryl ring systems are selected from the group ofacceptable substituents described below. An “arylene” and a“heteroarylene,” alone or as part of another substituent, mean adivalent radical derived from an aryl and heteroaryl, respectively. Aheteroaryl group substituent may be —O— bonded to a ring heteroatomnitrogen.

A fused ring heterocyloalkyl-aryl is an aryl fused to aheterocycloalkyl. A fused ring heterocycloalkyl-heteroaryl is aheteroaryl fused to a heterocycloalkyl. A fused ringheterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl.A fused ring heterocycloalkyl-heterocycloalkyl is a heterocycloalkylfused to another heterocycloalkyl. Fused ring heterocycloalkyl-aryl,fused ring heterocycloalkyl-heteroaryl, fused ringheterocycloalkyl-cycloalkyl, or fused ringheterocycloalkyl-heterocycloalkyl may each independently beunsubstituted or substituted with one or more of the substitutentsdescribed herein.

Spirocyclic rings are two or more rings wherein adjacent rings areattached through a single atom. The individual rings within spirocyclicrings may be identical or different. Individual rings in spirocyclicrings may be substituted or unsubstituted and may have differentsubstituents from other individual rings within a set of spirocyclicrings. Possible substituents for individual rings within spirocyclicrings are the possible substituents for the same ring when not part ofspirocyclic rings (e.g. substituents for cycloalkyl or heterocycloalkylrings). Spirocylic rings may be substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heterocycloalkylene andindividual rings within a spirocyclic ring group may be any of theimmediately previous list, including having all rings of one type (e.g.all rings being substituted heterocycloalkylene wherein each ring may bethe same or different substituted heterocycloalkylene). When referringto a spirocyclic ring system, heterocyclic spirocyclic rings means aspirocyclic rings wherein at least one ring is a heterocyclic ring andwherein each ring may be a different ring. When referring to aspirocyclic ring system, substituted spirocyclic rings means that atleast one ring is substituted and each substituent may optionally bedifferent.

The symbol “

” denotes the point of attachment of a chemical moiety to the remainderof a molecule or chemical formula.

The term “oxo,” as used herein, means an oxygen that is double bonded toa carbon atom.

The term “alkylsulfonyl,” as used herein, means a moiety having theformula —S(O₂)—R′, where R′ is a substituted or unsubstituted alkylgroup as defined above. R′ may have a specified number of carbons (e.g.,“C₁-C₄ alkylsulfonyl”).

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “cycloalkyl,”“heterocycloalkyl,” “aryl,” and “heteroaryl”) includes both substitutedand unsubstituted forms of the indicated radical. Preferred substituentsfor each type of radical are provided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be one or more of a variety of groups selectedfrom, but not limited to, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′,-halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″,—NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R′″,—ONR′R″, —NR′C(O)NR″NR′″R″″, —CN, —NO₂, —NR′SO₂R″, —NR′C(O)R″,—NR′C(O)—OR″, —NR′OR″, in a number ranging from zero to (2m′+1), wherem′ is the total number of carbon atoms in such radical. R, R′, R″, R′″,and R″″ each preferably independently refer to hydrogen, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl (e.g., aryl substituted with 1-3 halogens),substituted or unsubstituted heteroaryl, substituted or unsubstitutedalkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When acompound described herein includes more than one R group, for example,each of the R groups is independently selected as are each R′, R″, R′″,and R″″ group when more than one of these groups is present. When R′ andR″ are attached to the same nitrogen atom, they can be combined with thenitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example,—NR′R″ includes, but is not limited to, 1-pyrrolidinyl and4-morpholinyl. From the above discussion of substituents, one of skillin the art will understand that the term “alkyl” is meant to includegroups including carbon atoms bound to groups other than hydrogengroups, such as haloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl (e.g.,—C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and the like).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are varied and areselected from, for example: —OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″,—OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′,—NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″, —NR—C(NR′R″)═NR′″,—S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R′″, —ONR′R″,—NR′C(O)NR″NR′″R″″, —CN, —NO₂, —R′, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy,and fluoro(C₁-C₄)alkyl, —NR′SO₂R″, —NR′C(O)R″, —NR′C(O)—OR″, —NR′OR″, ina number ranging from zero to the total number of open valences on thearomatic ring system; and where R′, R″, R′″, and R″″ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl. When a compound described herein includes more than one Rgroup, for example, each of the R groups is independently selected asare each R′, R″, R′″, and R″″ groups when more than one of these groupsis present.

Substituents for rings (e.g. cycloalkyl, heterocycloalkyl, aryl,heteroaryl, cycloalkylene, heterocycloalkylene, arylene, orheteroarylene) may be depicted as substituents on the ring rather thanon a specific atom of a ring (commonly referred to as a floatingsubstituent). In such a case, the substituent may be attached to any ofthe ring atoms (obeying the rules of chemical valency) and in the caseof fused rings or spirocyclic rings, a substituent depicted asassociated with one member of the fused rings or spirocyclic rings (afloating substituent on a single ring), may be a substituent on any ofthe fused rings or spirocyclic rings (a floating substituent on multiplerings). When a substituent is attached to a ring, but not a specificatom (a floating substituent), and a subscript for the substituent is aninteger greater than one, the multiple substituents may be on the sameatom, same ring, different atoms, different fused rings, differentspirocyclic rings, and each substituent may optionally be different.Where a point of attachment of a ring to the remainder of a molecule isnot limited to a single atom (a floating substituent), the attachmentpoint may be any atom of the ring and in the case of a fused ring orspirocyclic ring, any atom of any of the fused rings or spirocyclicrings while obeying the rules of chemical valency. Where a ring, fusedrings, or spirocyclic rings contain one or more ring heteroatoms and thering, fused rings, or spirocyclic rings are shown with one more floatingsubstituents (including, but not limited to, points of attachment to theremainder of the molecule), the floating substituents may be bonded tothe heteroatoms. Where the ring heteroatoms are shown bound to one ormore hydrogens (e.g. a ring nitrogen with two bonds to ring atoms and athird bond to a hydrogen) in the structure or formula with the floatingsubstituent, when the heteroatom is bonded to the floating substituent,the substituent will be understood to replace the hydrogen, whileobeying the rules of chemical valency.

Two or more substituents may optionally be joined to form aryl,heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-calledring-forming substituents are typically, though not necessarily, foundattached to a cyclic base structure. In one embodiment, the ring-formingsubstituents are attached to adjacent members of the base structure. Forexample, two ring-forming substituents attached to adjacent members of acyclic base structure create a fused ring structure. In anotherembodiment, the ring-forming substituents are attached to a singlemember of the base structure. For example, two ring-forming substituentsattached to a single member of a cyclic base structure create aspirocyclic structure. In yet another embodiment, the ring-formingsubstituents are attached to non-adjacent members of the base structure.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally form a ring of the formula -T-C(O)—(CRR′)_(q)—U—, whereinT and U are independently —NR—, —O—, —CRR′—, or a single bond, and q isan integer of from 0 to 3. Alternatively, two of the substituents onadjacent atoms of the aryl or heteroaryl ring may optionally be replacedwith a substituent of the formula -A-(CH₂)_(r)—B—, wherein A and B areindependently —CRR′—, —O—, —NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′—, or asingle bond, and r is an integer of from 1 to 4. One of the single bondsof the new ring so formed may optionally be replaced with a double bond.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula —(CRR′)_(s)—X′— (C″R″R′″)_(d)—, where s and d are independentlyintegers of from 0 to 3, and X′ is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or—S(O)₂NR′—. The substituents R, R′, R″, and R′″ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.

As used herein, the terms “heteroatom” or “ring heteroatom” are meant toinclude oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), andsilicon (Si).

A “substituent group,” as used herein, means a group selected from thefollowing moieties:

-   -   (A) oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂, —CHBr₂,        —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,        —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,        —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,        —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,        —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, unsubstituted alkyl        (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted        heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered        heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted        cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆        cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8        membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or        5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g.,        C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or unsubstituted heteroaryl        (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl,        or 5 to 6 membered heteroaryl), and    -   (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,        heteroaryl, substituted with at least one substituent selected        from:        -   (i) oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂, —CHBr₂,            —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,            —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,            —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,            —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂,            —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F,            —N₃, unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or            C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8            membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4            membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈            cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),            unsubstituted heterocycloalkyl (e.g., 3 to 8 membered            heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to            6 membered heterocycloalkyl), unsubstituted aryl (e.g.,            C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or unsubstituted            heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9            membered heteroaryl, or 5 to 6 membered heteroaryl), and        -   (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,            heteroaryl, substituted with at least one substituent            selected from:            -   (a) oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂,                —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN,                —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,                —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂,                —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃,                —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,                —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, unsubstituted                alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),                unsubstituted heteroalkyl (e.g., 2 to 8 membered                heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4                membered heteroalkyl), unsubstituted cycloalkyl (e.g.,                C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆                cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to                8 membered heterocycloalkyl, 3 to 6 membered                heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),                unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or                phenyl), or unsubstituted heteroaryl (e.g., 5 to 10                membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to                6 membered heteroaryl), and        -   (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,            heteroaryl, substituted with at least one substituent            selected from: oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃,            —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I,            —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,            —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,            —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃,            —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I,            —OCH₂F, —N₃, unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆            alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g., 2            to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2            to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g.,            C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),            unsubstituted heterocycloalkyl (e.g., 3 to 8 membered            heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to            6 membered heterocycloalkyl), unsubstituted aryl (e.g.,            C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or unsubstituted            heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9            membered heteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, a “substituent group,” as used herein, means a groupselected from the following moieties:

-   -   (A) oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂, —CHBr₂,        —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,        —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,        —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,        —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,        —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, unsubstituted alkyl        (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted        heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered        heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted        cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆        cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8        membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or        5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g.,        C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or unsubstituted heteroaryl        (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl,        or 5 to 6 membered heteroaryl), and    -   (B) alkyl (e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),        heteroalkyl (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8        membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or        4 to 5 membered), cycloalkyl (e.g., C₃-C₁₀, C₃-C₈, C₃-C₆, C₄-C₆,        or C₅-C₆), heterocycloalkyl (e.g., 3 to 10 membered, 3 to 8        membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or        5 to 6 membered), aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or        heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9        membered, or 5 to 6 membered), substituted with at least one        substituent selected from:        -   (i) oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂, —CHBr₂,            —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,            —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,            —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,            —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂,            —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂CI, —OCH₂Br, —OCH₂I, —OCH₂F,            —N₃, unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or            C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8            membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4            membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈            cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),            unsubstituted heterocycloalkyl (e.g., 3 to 8 membered            heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to            6 membered heterocycloalkyl), unsubstituted aryl (e.g.,            C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or unsubstituted            heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9            membered heteroaryl, or 5 to 6 membered heteroaryl), and        -   (ii) alkyl (e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, or            C₁-C₂), heteroalkyl (e.g., 2 to 20 membered, 2 to 12            membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered,            2 to 3 membered, or 4 to 5 membered), cycloalkyl (e.g.,            C₃-C₁₀, C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), heterocycloalkyl            (e.g., 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4            to 6 membered, 4 to 5 membered, or 5 to 6 membered), aryl            (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or heteroaryl (e.g., 5 to            12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6            membered), substituted with at least one substituent            selected from:            -   (a) oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂,                —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN,                —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,                —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂,                —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃,                —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,                —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, unsubstituted                alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),                unsubstituted heteroalkyl (e.g., 2 to 8 membered                heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4                membered heteroalkyl), unsubstituted cycloalkyl (e.g.,                C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆                cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to                8 membered heterocycloalkyl, 3 to 6 membered                heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),                unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or                phenyl), or unsubstituted heteroaryl (e.g., 5 to 10                membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to                6 membered heteroaryl), and            -   (b) alkyl (e.g., C₁-C₂₀, C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₄, or                C₁-C₂), heteroalkyl (e.g., 2 to 20 membered, 2 to 12                membered, 2 to 8 membered, 2 to 6 membered, 4 to 6                membered, 2 to 3 membered, or 4 to 5 membered),                cycloalkyl (e.g., C₃-C₁₀, C₃-C₈, C₃-C₆, C₄-C₆, or                C₅-C₆), heterocycloalkyl (e.g., 3 to 10 membered, 3 to 8                membered, 3 to 6 membered, 4 to 6 membered, 4 to 5                membered, or 5 to 6 membered), aryl (e.g., C₆-C₁₂,                C₆-C₁₀, or phenyl), or heteroaryl (e.g., 5 to 12                membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6                membered), substituted with at least one substituent                selected from: oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃,                —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F,                —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,                —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂,                —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃,                —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,                —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, unsubstituted                alkyl (e.g., C₁-C₅ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),                unsubstituted heteroalkyl (e.g., 2 to 8 membered                heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4                membered heteroalkyl), unsubstituted cycloalkyl (e.g.,                C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆                cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to                8 membered heterocycloalkyl, 3 to 6 membered                heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),                unsubstituted aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or                phenyl), or unsubstituted heteroaryl (e.g., 5 to 10                membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to                6 membered heteroaryl).

A “size-limited substituent” or “size-limited substituent group,” asused herein, means a group selected from all of the substituentsdescribed above for a “substituent group,” wherein each substituted orunsubstituted alkyl is a substituted or unsubstituted C₁-C₂₀ alkyl, eachsubstituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl, eachsubstituted or unsubstituted aryl is a substituted or unsubstitutedC₆-C₁₀ aryl, and each substituted or unsubstituted heteroaryl is asubstituted or unsubstituted 5 to 10 membered heteroaryl.

A “lower substituent” or “lower substituent group,” as used herein,means a group selected from all of the substituents described above fora “substituent group,” wherein each substituted or unsubstituted alkylis a substituted or unsubstituted C₁-C₅ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7membered heterocycloalkyl, each substituted or unsubstituted aryl is asubstituted or unsubstituted C₆-C₁₀ aryl, and each substituted orunsubstituted heteroaryl is a substituted or unsubstituted 5 to 9membered heteroaryl.

In some embodiments, each substituted group described in the compoundsherein is substituted with at least one substituent group. Morespecifically, in some embodiments, each substituted alkyl, substitutedheteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl,substituted aryl, substituted heteroaryl, substituted alkylene,substituted heteroalkylene, substituted cycloalkylene, substitutedheterocycloalkylene, substituted arylene, and/or substitutedheteroarylene described in the compounds herein are substituted with atleast one substituent group. In other embodiments, at least one or allof these groups are substituted with at least one size-limitedsubstituent group. In other embodiments, at least one or all of thesegroups are substituted with at least one lower substituent group.

In other embodiments of the compounds herein, each substituted orunsubstituted alkyl may be a substituted or unsubstituted C₁-C₂₀ alkyl,each substituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl, eachsubstituted or unsubstituted aryl is a substituted or unsubstitutedC₆-C₁₀ aryl, and/or each substituted or unsubstituted heteroaryl is asubstituted or unsubstituted 5 to 10 membered heteroaryl. In someembodiments of the compounds herein, each substituted or unsubstitutedalkylene is a substituted or unsubstituted C₁-C₂₀ alkylene, eachsubstituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 20 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₈cycloalkylene, each substituted or unsubstituted heterocycloalkylene isa substituted or unsubstituted 3 to 8 membered heterocycloalkylene, eachsubstituted or unsubstituted arylene is a substituted or unsubstitutedC₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroaryleneis a substituted or unsubstituted 5 to 10 membered heteroarylene.

In some embodiments, each substituted or unsubstituted alkyl is asubstituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7membered heterocycloalkyl, each substituted or unsubstituted aryl is asubstituted or unsubstituted C₆-C₁₀ aryl, and/or each substituted orunsubstituted heteroaryl is a substituted or unsubstituted 5 to 9membered heteroaryl. In some embodiments, each substituted orunsubstituted alkylene is a substituted or unsubstituted C₁-C₈ alkylene,each substituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 8 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₇cycloalkylene, each substituted or unsubstituted heterocycloalkylene isa substituted or unsubstituted 3 to 7 membered heterocycloalkylene, eachsubstituted or unsubstituted arylene is a substituted or unsubstitutedC₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroaryleneis a substituted or unsubstituted 5 to 9 membered heteroarylene. In someembodiments, the compound is a chemical species set forth in theapplication (e.g., Examples section, figures, or tables below).

In embodiments, a substituted or unsubstituted moiety (e.g., substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene, substituted orunsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, and/orsubstituted or unsubstituted heteroarylene) is unsubstituted (e.g., isan unsubstituted alkyl, unsubstituted heteroalkyl, unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl,unsubstituted heteroaryl, unsubstituted alkylene, unsubstitutedheteroalkylene, unsubstituted cycloalkylene, unsubstitutedheterocycloalkylene, unsubstituted arylene, and/or unsubstitutedheteroarylene, respectively). In embodiments, a substituted orunsubstituted moiety (e.g., substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene, substituted or unsubstituted cycloalkylene, substitutedor unsubstituted heterocycloalkylene, substituted or unsubstitutedarylene, and/or substituted or unsubstituted heteroarylene) issubstituted (e.g., is a substituted alkyl, substituted heteroalkyl,substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl,substituted heteroaryl, substituted alkylene, substitutedheteroalkylene, substituted cycloalkylene, substitutedheterocycloalkylene, substituted arylene, and/or substitutedheteroarylene, respectively).

In embodiments, a substituted moiety (e.g., substituted alkyl,substituted heteroalkyl, substituted cycloalkyl, substitutedheterocycloalkyl, substituted aryl, substituted heteroaryl, substitutedalkylene, substituted heteroalkylene, substituted cycloalkylene,substituted heterocycloalkylene, substituted arylene, and/or substitutedheteroarylene) is substituted with at least one substituent group,wherein if the substituted moiety is substituted with a plurality ofsubstituent groups, each substituent group may optionally be different.In embodiments, if the substituted moiety is substituted with aplurality of substituent groups, each substituent group is different.

In embodiments, a substituted moiety (e.g., substituted alkyl,substituted heteroalkyl, substituted cycloalkyl, substitutedheterocycloalkyl, substituted aryl, substituted heteroaryl, substitutedalkylene, substituted heteroalkylene, substituted cycloalkylene,substituted heterocycloalkylene, substituted arylene, and/or substitutedheteroarylene) is substituted with at least one size-limited substituentgroup, wherein if the substituted moiety is substituted with a pluralityof size-limited substituent groups, each size-limited substituent groupmay optionally be different. In embodiments, if the substituted moietyis substituted with a plurality of size-limited substituent groups, eachsize-limited substituent group is different.

In embodiments, a substituted moiety (e.g., substituted alkyl,substituted heteroalkyl, substituted cycloalkyl, substitutedheterocycloalkyl, substituted aryl, substituted heteroaryl, substitutedalkylene, substituted heteroalkylene, substituted cycloalkylene,substituted heterocycloalkylene, substituted arylene, and/or substitutedheteroarylene) is substituted with at least one lower substituent group,wherein if the substituted moiety is substituted with a plurality oflower substituent groups, each lower substituent group may optionally bedifferent. In embodiments, if the substituted moiety is substituted witha plurality of lower substituent groups, each lower substituent group isdifferent.

In embodiments, a substituted moiety (e.g., substituted alkyl,substituted heteroalkyl, substituted cycloalkyl, substitutedheterocycloalkyl, substituted aryl, substituted heteroaryl, substitutedalkylene, substituted heteroalkylene, substituted cycloalkylene,substituted heterocycloalkylene, substituted arylene, and/or substitutedheteroarylene) is substituted with at least one substituent group,size-limited substituent group, or lower substituent group; wherein ifthe substituted moiety is substituted with a plurality of groupsselected from substituent groups, size-limited substituent groups, andlower substituent groups; each substituent group, size-limitedsubstituent group, and/or lower substituent group may optionally bedifferent. In embodiments, if the substituted moiety is substituted witha plurality of groups selected from substituent groups, size-limitedsubstituent groups, and lower substituent groups; each substituentgroup, size-limited substituent group, and/or lower substituent group isdifferent.

Certain compounds of the present disclosure possess asymmetric carbonatoms (optical or chiral centers) or double bonds; the enantiomers,racemates, diastereomers, tautomers, geometric isomers, stereoisometricforms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers areencompassed within the scope of the present disclosure. The compounds ofthe present disclosure do not include those that are known in art to betoo unstable to synthesize and/or isolate. The present disclosure ismeant to include compounds in racemic and optically pure forms.Optically active (R)- and (S)-, or (D)- and (L)-isomers may be preparedusing chiral synthons or chiral reagents, or resolved using conventionaltechniques. When the compounds described herein contain olefinic bondsor other centers of geometric asymmetry, and unless specified otherwise,it is intended that the compounds include both E and Z geometricisomers.

As used herein, the term “isomers” refers to compounds having the samenumber and kind of atoms, and hence the same molecular weight, butdiffering in respect to the structural arrangement or configuration ofthe atoms.

The term “tautomer,” as used herein, refers to one of two or morestructural isomers which exist in equilibrium and which are readilyconverted from one isomeric form to another.

It will be apparent to one skilled in the art that certain compounds ofthis disclosure may exist in tautomeric forms, all such tautomeric formsof the compounds being within the scope of the disclosure.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of thedisclosure.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbonare within the scope of this disclosure.

The compounds of the present disclosure may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I), or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present disclosure, whether radioactive or not, areencompassed within the scope of the present disclosure.

It should be noted that throughout the application that alternatives arewritten in Markush groups, for example, each amino acid position thatcontains more than one possible amino acid. It is specificallycontemplated that each member of the Markush group should be consideredseparately, thereby comprising another embodiment, and the Markush groupis not to be read as a single unit.

As used herein, the term “bioconjugate reactive moiety” and“bioconjugate reactive group” refers to a moiety or group capable offorming a bioconjugate (e.g., covalent linker) as a result of theassociation between atoms or molecules of bioconjugate reactive groups.The association can be direct or indirect. For example, a conjugatebetween a first bioconjugate reactive group (e.g., —NH₂, —COOH,—N-hydroxysuccinimide, or -maleimide) and a second bioconjugate reactivegroup (e.g., sulfhydryl, sulfur-containing amino acid, amine, aminesidechain containing amino acid, or carboxylate) provided herein can bedirect, e.g., by covalent bond or linker (e.g. a first linker of secondlinker), or indirect, e.g., by non-covalent bond (e.g. electrostaticinteractions (e.g. ionic bond, hydrogen bond, halogen bond), van derWaals interactions (e.g. dipole-dipole, dipole-induced dipole, Londondispersion), ring stacking (pi effects), hydrophobic interactions andthe like). In embodiments, bioconjugates or bioconjugate linkers areformed using bioconjugate chemistry (i.e. the association of twobioconjugate reactive groups) including, but are not limited tonucleophilic substitutions (e.g., reactions of amines and alcohols withacyl halides, active esters), electrophilic substitutions (e.g., enaminereactions) and additions to carbon-carbon and carbon-heteroatom multiplebonds (e.g., Michael reaction, Diels-Alder addition). These and otheruseful reactions are discussed in, for example, March, ADVANCED ORGANICCHEMISTRY, 3rd Ed., John Wiley & Sons, New York, 1985; Hermanson,BIOCONJUGATE TECHNIQUES, Academic Press, San Diego, 1996; and Feeney etal., MODIFICATION OF PROTEINS; Advances in Chemistry Series, Vol. 198,American Chemical Society, Washington, D.C. , 1982. In embodiments, thefirst bioconjugate reactive group (e.g., maleimide moiety) is covalentlyattached to the second bioconjugate reactive group (e.g. a sulfhydryl).In embodiments, the first bioconjugate reactive group (e.g., haloacetylmoiety) is covalently attached to the second bioconjugate reactive group(e.g. a sulfhydryl). In embodiments, the first bioconjugate reactivegroup (e.g., pyridyl moiety) is covalently attached to the secondbioconjugate reactive group (e.g. a sulfhydryl). In embodiments, thefirst bioconjugate reactive group (e.g., —N-hydroxysuccinimide moiety)is covalently attached to the second bioconjugate reactive group (e.g.an amine). In embodiments, the first bioconjugate reactive group (e.g.,maleimide moiety) is covalently attached to the second bioconjugatereactive group (e.g. a sulfhydryl). In embodiments, the firstbioconjugate reactive group (e.g., -sulfo-N-hydroxysuccinimide moiety)is covalently attached to the second bioconjugate reactive group (e.g.an amine).

Useful bioconjugate reactive moieties used for bioconjugate chemistriesherein include, for example:

-   -   (a) carboxyl groups and various derivatives thereof including,        but not limited to, N-hydroxysuccinimide esters,        N-hydroxybenztriazole esters, acid halides, acyl imidazoles,        thioesters, p-nitrophenyl esters, alkyl, alkenyl, alkynyl and        aromatic esters; (b) hydroxyl groups which can be converted to        esters, ethers, aldehydes, etc.; (c) haloalkyl groups wherein        the halide can be later displaced with a nucleophilic group such        as, for example, an amine, a carboxylate anion, thiol anion,        carbanion, or an alkoxide ion, thereby resulting in the covalent        attachment of a new group at the site of the halogen atom; (d)        dienophile groups which are capable of participating in        Diels-Alder reactions such as, for example, maleimido or        maleimide groups; (e) aldehyde or ketone groups such that        subsequent derivatization is possible via formation of carbonyl        derivatives such as, for example, imines, hydrazones,        semicarbazones or oximes, or via such mechanisms as Grignard        addition or alkyllithium addition; (f) sulfonyl halide groups        for subsequent reaction with amines, for example, to form        sulfonamides; (g) thiol groups, which can be converted to        disulfides, reacted with acyl halides, or bonded to metals such        as gold, or react with maleimides; (h) amine or sulfhydryl        groups (e.g., present in cysteine), which can be, for example,        acylated, alkylated or oxidized; (i) alkenes, which can undergo,        for example, cycloadditions, acylation, Michael addition,        etc; (j) epoxides, which can react with, for example, amines and        hydroxyl compounds; (k) phosphoramidites and other standard        functional groups useful in nucleic acid synthesis; (l) metal        silicon oxide bonding; (m) metal bonding to reactive phosphorus        groups (e.g. phosphines) to form, for example, phosphate diester        bonds; (n) azides coupled to alkynes using copper catalyzed        cycloaddition click chemistry; (o) biotin conjugate can react        with avidin or strepavidin to form a avidin-biotin complex or        streptavidin-biotin complex.

The bioconjugate reactive groups can be chosen such that they do notparticipate in, or interfere with, the chemical stability of theconjugate described herein. Alternatively, a reactive functional groupcan be protected from participating in the crosslinking reaction by thepresence of a protecting group. In embodiments, the bioconjugatecomprises a molecular entity derived from the reaction of an unsaturatedbond, such as a maleimide, and a sulfhydryl group.

“Analog,” or “analogue” is used in accordance with its plain ordinarymeaning within Chemistry and Biology and refers to a chemical compoundthat is structurally similar to another compound (i.e., a so-called“reference” compound) but differs in composition, e.g., in thereplacement of one atom by an atom of a different element, or in thepresence of a particular functional group, or the replacement of onefunctional group by another functional group, or the absolutestereochemistry of one or more chiral centers of the reference compound.Accordingly, an analog is a compound that is similar or comparable infunction and appearance but not in structure or origin to a referencecompound.

The terms “a” or “an,” as used in herein means one or more. In addition,the phrase “substituted with a[n],” as used herein, means the specifiedgroup may be substituted with one or more of any or all of the namedsubstituents. For example, where a group, such as an alkyl or heteroarylgroup, is “substituted with an unsubstituted C₁-C₂₀ alkyl, orunsubstituted 2 to 20 membered heteroalkyl,” the group may contain oneor more unsubstituted C₁-C₂₀ alkyls, and/or one or more unsubstituted 2to 20 membered heteroalkyls.

Moreover, where a moiety is substituted with an R substituent, the groupmay be referred to as “R-substituted.” Where a moiety is R-substituted,the moiety is substituted with at least one R substituent and each Rsubstituent is optionally different. Where a particular R group ispresent in the description of a chemical genus (such as Formula (I)), aRoman alphabetic symbol may be used to distinguish each appearance ofthat particular R group. For example, where multiple R¹³ substituentsare present, each R¹³ substituent may be distinguished as R^(13A),R^(13B), R^(13C), R^(13D), etc., wherein each of R^(13A), R^(13B),R^(13C), R^(13D), etc. is defined within the scope of the definition ofR¹³ and optionally differently.

A “detectable agent” or “detectable moiety” is a substance, element,compound, or composition; or moiety thereof, detectable by appropriatemeans such as spectroscopic, photochemical, biochemical, immunochemical,chemical, magnetic resonance imaging, or other physical means. Forexample, useful detectable agents include ¹⁸F, ³²P, ³³P, ⁴⁵Ti, ⁴⁷Sc,⁵²Fe, ⁵⁹Fe, ⁶²Cu, ⁶⁴Cu, ⁶⁷Cu, ⁶⁷Ga, ⁶⁸Ga, ⁷⁷As, ⁸⁶Y, ⁹⁰Y, ⁸⁹Sr, ⁸⁹Zr,⁹⁴Tc, ⁹⁴Tc, ⁹⁹mTc, ⁹⁹Mo, ¹⁰⁵Pd, ¹⁰⁵Rh, ¹¹¹Ag, ¹¹¹In, ¹²³I, ¹²⁴I, ¹²⁵I,¹³¹I, ¹⁴²Pr, ¹⁴³Pr, ¹⁴⁹Pm, ¹⁵³Sm, ¹⁵⁴⁻¹⁵⁸¹Gd, ¹⁶¹Tb, ¹⁶⁶Dy, ¹⁶⁶Ho,¹⁶⁹Er, ¹⁷⁵Lu, ¹⁷⁷Lu, ¹⁸⁶Re, ¹⁸⁸Re, ¹⁸⁹Re, ¹⁹⁴Ir, ¹⁹⁸Au, ¹⁹⁹Au, ²¹¹At,²¹¹Pb, ²¹²Bi, ²¹²Pb, ²¹³Bi, ²²³Ra, ²²⁵Ac, Cr, V, Mn, Fe, Co, Ni, Cu, La,Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, ³²P, fluorophore(e.g. fluorescent dyes), electron-dense reagents, enzymes (e.g., ascommonly used in an ELISA), biotin, digoxigenin, paramagnetic molecules,paramagnetic nanoparticles, ultrasmall superparamagnetic iron oxide(“USPIO”) nanoparticles, USPIO nanoparticle aggregates,superparamagnetic iron oxide (“SPIO”) nanoparticles, SPIO nanoparticleaggregates, monochrystalline iron oxide nanoparticles, monochrystallineiron oxide, nanoparticle contrast agents, liposomes or other deliveryvehicles containing Gadolinium chelate (“Gd-chelate”) molecules,Gadolinium, radioisotopes, radionuclides (e.g. carbon-11, nitrogen-13,oxygen-15, fluorine-18, rubidium-82), fluorodeoxyglucose (e.g.fluorine-18 labeled), any gamma ray emitting radionuclides,positron-emitting radionuclide, radiolabeled glucose, radiolabeledwater, radiolabeled ammonia, biocolloids, microbubbles (e.g. includingmicrobubble shells including albumin, galactose, lipid, and/or polymers;microbubble gas core including air, heavy gas(es), perfluorcarbon,nitrogen, octafluoropropane, perflexane lipid microsphere, perflutren,etc.), iodinated contrast agents (e.g. iohexol, iodixanol, ioversol,iopamidol, ioxilan, iopromide, diatrizoate, metrizoate, ioxaglate),barium sulfate, thorium dioxide, gold, gold nanoparticles, goldnanoparticle aggregates, fluorophores, two-photon fluorophores, orhaptens and proteins or other entities which can be made detectable,e.g., by incorporating a radiolabel into a peptide or antibodyspecifically reactive with a target peptide. A detectable moiety is amonovalent detectable agent or a detectable agent capable of forming abond with another composition.

Radioactive substances (e.g., radioisotopes) that may be used as imagingand/or labeling agents in accordance with the embodiments of thedisclosure include, but are not limited to, ¹⁸F, ³²P, ³³P, ⁴⁵Ti, ⁴⁷Sc,⁵²Fe, ⁵⁹Fe, ⁶²Cu, ⁶⁴Cu, ⁶⁷Cu, ⁶⁷Ga, ⁶⁸Ga, ⁷⁷As, ⁸⁶Y, ⁹⁰Y, ⁸⁹Sr, ⁸⁹Zr,⁹⁴Tc, ⁹⁴Tc, ⁹⁹mTc ⁹⁹Mo, ¹⁰⁵Pd, ¹⁰⁵Rh, ¹¹¹Ag, ¹¹¹In ¹²³I, ¹²⁴I, ¹²⁵I,¹³¹I, ¹⁴²Pr, ¹⁴³Pr, ¹⁴⁹Pm, ¹⁵³Sm, ¹⁵⁴⁻¹⁵⁸¹Gd, ¹⁶¹Tb, ¹⁶⁶Dy, ¹⁶⁶Ho,¹⁶⁹Er, ¹⁷⁵Lu, ¹⁷⁷Lu, ¹⁸⁶Re, ¹⁸⁸Re, ¹⁸⁹Re, ¹⁹⁴I, ¹⁹⁸Au, ¹⁹⁹Au, ²¹¹At,²¹¹Pb, ²¹²Bi, ²¹²Pb, ²¹³Bi, ²²³Ra and ²²⁵Ac. Paramagnetic ions that maybe used as additional imaging agents in accordance with the embodimentsof the disclosure include, but are not limited to, ions of transitionand lanthanide metals (e.g. metals having atomic numbers of 21-29, 42,43, 44, or 57-71). These metals include ions of Cr, V, Mn, Fe, Co, Ni,Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu.

Descriptions of compounds of the present disclosure are limited byprinciples of chemical bonding known to those skilled in the art.Accordingly, where a group may be substituted by one or more of a numberof substituents, such substitutions are selected so as to comply withprinciples of chemical bonding and to give compounds which are notinherently unstable and/or would be known to one of ordinary skill inthe art as likely to be unstable under ambient conditions, such asaqueous, neutral, and several known physiological conditions. Forexample, a heterocycloalkyl or heteroaryl is attached to the remainderof the molecule via a ring heteroatom in compliance with principles ofchemical bonding known to those skilled in the art thereby avoidinginherently unstable compounds.

A person of ordinary skill in the art will understand when a variable(e.g., moiety or linker) of a compound or of a compound genus (e.g., agenus described herein) is described by a name or formula of astandalone compound with all valencies filled, the unfilled valence(s)of the variable will be dictated by the context in which the variable isused. For example, when a variable of a compound as described herein isconnected (e.g., bonded) to the remainder of the compound through asingle bond, that variable is understood to represent a monovalent form(i.e., capable of forming a single bond due to an unfilled valence) of astandalone compound (e.g., if the variable is named “methane” in anembodiment but the variable is known to be attached by a single bond tothe remainder of the compound, a person of ordinary skill in the artwould understand that the variable is actually a monovalent form ofmethane, i.e., methyl or —CH₃). Likewise, for a linker variable (e.g.,L¹, L², or L³ as described herein), a person of ordinary skill in theart will understand that the variable is the divalent form of astandalone compound (e.g., if the variable is assigned to “PEG” or“polyethylene glycol” in an embodiment but the variable is connected bytwo separate bonds to the remainder of the compound, a person ofordinary skill in the art would understand that the variable is adivalent (i.e., capable of forming two bonds through two unfilledvalences) form of PEG instead of the standalone compound PEG).

As used herein, the term “salt” refers to acid or base salts of thecompounds used in the methods of the present invention. Illustrativeexamples of acceptable salts are mineral acid (hydrochloric acid,hydrobromic acid, phosphoric acid, and the like) salts, organic acid(acetic acid, propionic acid, glutamic acid, citric acid and the like)salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like)salts.

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds that are prepared with relatively nontoxic acidsor bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present disclosurecontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentdisclosure contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and thelike. Also included are salts of amino acids such as arginate and thelike, and salts of organic acids like glucuronic or galactunoric acidsand the like (see, for example, Berge et al., “Pharmaceutical Salts”,Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specificcompounds of the present disclosure contain both basic and acidicfunctionalities that allow the compounds to be converted into eitherbase or acid addition salts.

Thus, the compounds of the present disclosure may exist as salts, suchas with pharmaceutically acceptable acids. The present disclosureincludes such salts. Non-limiting examples of such salts includehydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates,nitrates, maleates, acetates, citrates, fumarates, proprionates,tartrates (e.g., (+)-tartrates, (−)-tartrates, or mixtures thereofincluding racemic mixtures), succinates, benzoates, and salts with aminoacids such as glutamic acid, and quaternary ammonium salts (e.g. methyliodide, ethyl iodide, and the like). These salts may be prepared bymethods known to those skilled in the art.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compound maydiffer from the various salt forms in certain physical properties, suchas solubility in polar solvents.

In addition to salt forms, the present disclosure provides compounds,which are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentdisclosure. Prodrugs of the compounds described herein may be convertedin vivo after administration. Additionally, prodrugs can be converted tothe compounds of the present disclosure by chemical or biochemicalmethods in an ex vivo environment, such as, for example, when contactedwith a suitable enzyme or chemical reagent.

Certain compounds of the present disclosure can exist in unsolvatedforms as well as solvated forms, including hydrated forms. In general,the solvated forms are equivalent to unsolvated forms and areencompassed within the scope of the present disclosure. Certaincompounds of the present disclosure may exist in multiple crystalline oramorphous forms. In general, all physical forms are equivalent for theuses contemplated by the present disclosure and are intended to bewithin the scope of the present disclosure.

“Pharmaceutically acceptable excipient” and “pharmaceutically acceptablecarrier” refer to a substance that aids the administration of an activeagent to and absorption by a subject and can be included in thecompositions of the present disclosure without causing a significantadverse toxicological effect on the patient. Non-limiting examples ofpharmaceutically acceptable excipients include water, NaCl, normalsaline solutions, lactated Ringer's, normal sucrose, normal glucose,binders, fillers, disintegrants, lubricants, coatings, sweeteners,flavors, salt solutions (such as Ringer's solution), alcohols, oils,gelatins, carbohydrates such as lactose, amylose or starch, fatty acidesters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, andthe like. Such preparations can be sterilized and, if desired, mixedwith auxiliary agents such as lubricants, preservatives, stabilizers,wetting agents, emulsifiers, salts for influencing osmotic pressure,buffers, coloring, and/or aromatic substances and the like that do notdeleteriously react with the compounds of the disclosure. One of skillin the art will recognize that other pharmaceutical excipients areuseful in the present disclosure.

The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.

Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

As used herein, the term “about” means a range of values including thespecified value, which a person of ordinary skill in the art wouldconsider reasonably similar to the specified value. In embodiments,about means within a standard deviation using measurements generallyacceptable in the art. In embodiments, about means a range extending to+/−10% of the specified value. In embodiments, about includes thespecified value.

A “TXNIP inhibitor” refers to a compound (e.g. compounds describedherein) that reduces the level of activity of TXNIP when compared to acontrol, such as absence of the compound or a compound with knowninactivity. In embodiments, a TXNIP inhibitor reduces the activity orfunction (e.g., thioredoxin binding) of the TXNIP protein. Inembodiments, a TXNIP inhibitor reduces the level of expression of TXNIP(e.g., in a cell).

“Contacting” is used in accordance with its plain ordinary meaning andrefers to the process of allowing at least two distinct species (e.g.chemical compounds including biomolecules or cells) to becomesufficiently proximal to react, interact or physically touch. It shouldbe appreciated; however, the resulting reaction product can be produceddirectly from a reaction between the added reagents or from anintermediate from one or more of the added reagents that can be producedin the reaction mixture.

The term “contacting” may include allowing two species to react,interact, or physically touch, wherein the two species may be a compoundas described herein and a protein or enzyme. In some embodiments,contacting includes allowing a compound described herein to interactwith a protein or enzyme that is involved in a signaling pathway.

As defined herein, the term “activation”, “activate”, “activating”,“activator” and the like in reference to a protein-inhibitor interactionmeans positively affecting (e.g. increasing) the activity or function ofthe protein relative to the activity or function of the protein in theabsence of the activator. In embodiments activation means positivelyaffecting (e.g. increasing) the concentration or levels of the proteinrelative to the concentration or level of the protein in the absence ofthe activator. The terms may reference activation, or activating,sensitizing, or up-regulating signal transduction or enzymatic activityor the amount of a protein decreased in a disease. Thus, activation mayinclude, at least in part, partially or totally increasing stimulation,increasing or enabling activation, or activating, sensitizing, orup-regulating signal transduction or enzymatic activity or the amount ofa protein associated with a disease (e.g., a protein which is decreasedin a disease relative to a non-diseased control). Activation mayinclude, at least in part, partially or totally increasing stimulation,increasing or enabling activation, or activating, sensitizing, orup-regulating signal transduction or enzymatic activity or the amount ofa protein

The terms “agonist,” “activator,” “upregulator,” etc. refer to asubstance capable of detectably increasing the expression or activity ofa given gene or protein. The agonist can increase expression or activity10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more in comparison to acontrol in the absence of the agonist. In certain instances, expressionor activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold orhigher than the expression or activity in the absence of the agonist.

As defined herein, the term “inhibition”, “inhibit”, “inhibiting” andthe like in reference to a protein-inhibitor interaction meansnegatively affecting (e.g. decreasing) the activity or function of theprotein relative to the activity or function of the protein in theabsence of the inhibitor. In embodiments inhibition means negativelyaffecting (e.g. decreasing) the concentration or levels of the proteinrelative to the concentration or level of the protein in the absence ofthe inhibitor. In embodiments, inhibition refers to reduction of adisease or symptoms of disease. In embodiments, inhibition refers to areduction in the activity of a particular protein target. Thus,inhibition includes, at least in part, partially or totally blockingstimulation, decreasing, preventing, or delaying activation, orinactivating, desensitizing, or down-regulating signal transduction orenzymatic activity or the amount of a protein. In embodiments,inhibition refers to a reduction of activity of a target proteinresulting from a direct interaction (e.g. an inhibitor binds to thetarget protein). In embodiments, inhibition refers to a reduction ofactivity of a target protein from an indirect interaction (e.g. aninhibitor binds to a protein that activates the target protein, therebypreventing target protein activation). A “TXNIP-TRX complex inhibitor”is a compound that negatively affects (e.g. decreases) the activity orfunction of the TXNIP-TRX complex relative to the activity or functionof TXNIP-TRX complex in the absence of the inhibitor. In embodiments, aTXNIP-TRX complex inhibitor prevents the formation of the TXNIP-TRXcomplex (e.g., prevents TXNIP from interacting with TRX). A “TXNIPexpression inhibitor” is a compound that negatively affects (e.g.decreases) the level of expression of TXNIP relative to the level ofexpression of TXNIP in the absence of the inhibitor.

The terms “inhibitor,” “repressor” or “antagonist” or “downregulator”interchangeably refer to a substance capable of detectably decreasingthe expression or activity of a given gene or protein. The antagonistcan decrease expression or activity 10%, 20%, 30%, 40%, 50%, 60%, 70%,80%, 90% or more in comparison to a control in the absence of theantagonist. In certain instances, expression or activity is 1.5-fold,2-fold, 3-fold, 4-fold, 5-fold, 10-fold or lower than the expression oractivity in the absence of the antagonist.

The terms “thioredoxin” and “TXN” and “TRX” refer to a protein(including homologs, isoforms, and functional fragments thereof) withthioredoxin activity. The term includes any recombinant ornaturally-occurring form of thioredoxin or variants thereof thatmaintain thioredoxin activity (e.g. within at least 30%, 40%, 50%, 60%,70%, 80%, 90%, 95%, or 100% activity compared to wildtype thioredoxin).In embodiments, the thioredoxin protein encoded by the thioredoxin genehas the amino acid sequence set forth in or corresponding to Entrez7295, UniProt P10599, or RefSeq (protein) NP_003320. In embodiments, thethioredoxin gene has the nucleic acid sequence set forth in RefSeq(mRNA) NM_003329. In embodiments, the amino acid sequence or nucleicacid sequence is the sequence known at the time of filing of the presentapplication. In embodiments, the sequence corresponds to NP_003320.2. Inembodiments, the sequence corresponds to NM_003329.3. In embodiments,the thioredoxin protein encoded by the thioredoxin gene has the aminoacid sequence set forth in or corresponding RefSeq (protein)NP_001231867. In embodiments, the thioredoxin gene has the nucleic acidsequence set forth in RefSeq (mRNA) NM_001244938. In embodiments, theamino acid sequence or nucleic acid sequence is the sequence known atthe time of filing of the present application. In embodiments, thesequence corresponds to NP_001231867.1. In embodiments, the sequencecorresponds to NM_001244938.1. In embodiments, the thioredoxin is ahuman thioredoxin. In embodiments, the thioredoxin corresponds to thesequence:

(SEQ ID NO: 1) MVKQIESKTAFQEALDAAGDKLVVVDFSATWCGPCKMIKPFFHSLSEKYSNVIFLEVDVDDCQDVASECEVKCMPTFQFFKKGQKVGEFSGANKEKLEAT INELV.

The terms “Thioredoxin-interacting protein” and “TXNIP” refer to aprotein (including homologs, isoforms, and functional fragments thereof)which interacts with thioredoxin. The term includes any recombinant ornaturally-occurring form of TXNIP or variants thereof that maintainTXNIP activity (e.g. within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%,95%, or 100% activity compared to wildtype TXNIP). In embodiments, theTXNIP protein encoded by the TXNIP gene has the amino acid sequence setforth in or corresponding to Entrez 10628, UniProt Q9H3M7, RefSeq(protein) NP_006463, or RefSeq (protein) NP_001300901. In embodiments,the TXNIP gene has the nucleic acid sequence set forth in RefSeq (mRNA)NM_006472. In embodiments, the TXNIP gene has the nucleic acid sequenceset forth in RefSeq (mRNA) NM_001313972. In embodiments, the amino acidsequence or nucleic acid sequence is the sequence known at the time offiling of the present application. In embodiments, the sequencecorresponds to NP_001300901. In embodiments, the sequence corresponds toNP_006463. In embodiments, the TXNIP protein encoded by the TXNIP genehas the amino acid sequence set forth in or corresponding RefSeq(protein) NP_00130901. In embodiments, the TXNIP gene has the nucleicacid sequence set forth in RefSeq (mRNA) NM_006472. In embodiments, theamino acid sequence or nucleic acid sequence is the sequence known atthe time of filing of the present application. In embodiments, thesequence corresponds to NP_001231867.1. In embodiments, the TXNIPprotein corresponds to the sequence:

(SEQ ID NO: 2) MVMFKKIKSFEVVFNDPEKVYGSGEKVAGRVIVEVCEVTRVKAVRILACGVAKVLWMQGSQQCKQTSEYLRYEDTLLLEDQPTGENEMVIMRPGNKYEYKFGFELPQGPLGTSFKGKYGCVDYWVKAFLDRPSQPTQETKKNFEVVDLVDVNTPDLMAPVSAKKEKKVSCMFIPDGRVSVSARIDRKGFCEGDEISIHADFENTCSRIVVPKAAIVARHTYLANGQTKVLTQKLSSVRGNHIISGTCASWRGKSLRVQKIRPSILGCNILRVEYSLLIYVSVPGSKKVILDLPLVIGSRSGLSSRTSSMASRTSSEMSWVDLNIPDTPEAPPCYMDVIPEDHRLESPTTPLLDDMDGSQDSPIFMYAPEFKFMPPPTYTEVDPCILNNNVQ.

The term “expression” includes any step involved in the production ofthe polypeptide including, but not limited to, transcription,post-transcriptional modification, translation, post-translationalmodification, and secretion. Expression can be detected usingconventional techniques for detecting protein (e.g., ELISA, Westernblotting, flow cytometry, immunofluorescence, immunohistochemistry,etc.).

The term “modulator” refers to a composition that increases or decreasesthe level of a target molecule or the function of a target molecule orthe physical state of the target of the molecule relative to the absenceof the modulator. The term “modulate” is used in accordance with itsplain ordinary meaning and refers to the act of changing or varying oneor more properties. “Modulation” refers to the process of changing orvarying one or more properties. For example, as applied to the effectsof a modulator on a target protein, to modulate means to change byincreasing or decreasing a property or function of the target moleculeor the amount of the target molecule.

The term “associated” or “associated with” in the context of a substanceor substance activity or function associated with a disease (e.g. aprotein associated disease, diabetes associated complication (e.g.,nephropathy, retinopathy, neuropathy, cardiovascular disease, andinflammation), metabolic disorder associated disease (e.g., diabetes,inflammatory disease, or infectious disease)) means that the disease iscaused by (in whole or in part), or a symptom of the disease is causedby (in whole or in part) the substance or substance activity orfunction. In embodiments, the TXNIP-associated disease is diabetes,diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, orcardiovascular disease. In embodiments, the TXNIP-TRX-associated diseaseis diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, orcardiovascular disease.

The term “aberrant” as used herein refers to different from normal. Whenused to describe enzymatic activity or protein function, aberrant refersto activity or function that is greater or less than a normal control orthe average of normal non-diseased control samples. Aberrant activitymay refer to an amount of activity that results in a disease, whereinreturning the aberrant activity to a normal or non-disease-associatedamount (e.g. by administering a compound or using a method as describedherein), results in reduction of the disease or one or more diseasesymptoms.

The term “signaling pathway” as used herein refers to a series ofinteractions between cellular and optionally extra-cellular components(e.g. proteins, nucleic acids, small molecules, ions, lipids) thatconveys a change in one component to one or more other components, whichin turn may convey a change to additional components, which isoptionally propogated to other signaling pathway components. Forexample, binding of a thioredoxin protein with a compound as describedherein may reduce the interactions between the thioredoxin protein anddownstream effectors or signaling pathway components, resulting inchanges in cell growth, proliferation, or survival.

In this disclosure, “comprises,” “comprising,” “containing” and “having”and the like can have the meaning ascribed to them in U.S. Patent lawand can mean “includes,” “including,” and the like. “Consistingessentially of” or “consists essentially” likewise has the meaningascribed in U.S. Patent law and the term is open-ended, allowing for thepresence of more than that which is recited so long as basic or novelcharacteristics of that which is recited is not changed by the presenceof more than that which is recited, but excludes prior art embodiments.

The terms “disease” or “condition” refer to a state of being or healthstatus of a patient or subject capable of being treated with thecompounds or methods provided herein. The disease may be diabetes. Thedisease may be a metabolic disorder. The disease may be an inflammatorydisease. The disease may be an infectious disease. In embodiments, thedisease is diabetes (e.g., type 1 diabetes or type 2 diabetes), insulinresistance, metabolic syndrome, atherosclerosis, obesity,hyperlipidemia, hyperglycemia, high serum triglycerides, and/or highblood pressure.

Examples of inflammatory diseases include autoimmune diseases,arthritis, rheumatoid arthritis, psoriatic arthritis, juvenileidiopathic arthritis, multiple sclerosis, systemic lupus erythematosus(SLE), myasthenia gravis, juvenile onset diabetes, diabetes mellitustype 1, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto'sthyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome,vasculitis, glomerulonephritis, auto-immune thyroiditis, Behcet'sdisease, Crohn's disease, ulcerative colitis, bullous pemphigoid,sarcoidosis, ichthyosis, Graves ophthalmopathy, inflammatory boweldisease, Addison's disease, Vitiligo, asthma, allergic asthma, acnevulgaris, celiac disease, chronic prostatitis, inflammatory boweldisease, pelvic inflammatory disease, reperfusion injury, ischemiareperfusion injury, stroke, sarcoidosis, transplant rejection,interstitial cystitis, atherosclerosis, scleroderma, and atopicdermatitis.

As used herein, the term “inflammatory disease” refers to a disease orcondition characterized by aberrant inflammation (e.g. an increasedlevel of inflammation compared to a control such as a healthy person notsuffering from a disease). Examples of inflammatory diseases includetraumatic brain injury, arthritis, rheumatoid arthritis, psoriaticarthritis, juvenile idiopathic arthritis, multiple sclerosis, systemiclupus erythematosus (SLE), myasthenia gravis, juvenile onset diabetes,diabetes mellitus type 1, Guillain-Barre syndrome, Hashimoto'sencephalitis, Hashimoto's thyroiditis, ankylosing spondylitis,psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis,auto-immune thyroiditis, Behcet's disease, Crohn's disease, ulcerativecolitis, bullous pemphigoid, sarcoidosis, ichthyosis, Gravesophthalmopathy, inflammatory bowel disease, Addison's disease, Vitiligo,asthma, asthma, allergic asthma, acne vulgaris, celiac disease, chronicprostatitis, inflammatory bowel disease, pelvic inflammatory disease,reperfusion injury, sarcoidosis, transplant rejection, interstitialcystitis, atherosclerosis, and atopic dermatitis. In embodiments, theinflammatory disease is inflammation.

The terms “treating”, or “treatment” refers to any indicia of success inthe therapy or amelioration of an injury, disease, pathology orcondition, including any objective or subjective parameter such asabatement; remission; diminishing of symptoms or making the injury,pathology or condition more tolerable to the patient; slowing in therate of degeneration or decline; making the final point of degenerationless debilitating; improving a patient's physical or mental well-being.The treatment or amelioration of symptoms can be based on objective orsubjective parameters; including the results of a physical examination,neuropsychiatric exams, and/or a psychiatric evaluation. The term“treating” and conjugations thereof, may include prevention of aninjury, pathology, condition, or disease. In embodiments, treating ispreventing. In embodiments, treating does not include preventing. Inembodiments, treating refers to treating a subject having a disease.

“Treating” or “treatment” as used herein (and as well-understood in theart) also broadly includes any approach for obtaining beneficial ordesired results in a subject's condition, including clinical results.Beneficial or desired clinical results can include, but are not limitedto, alleviation or amelioration of one or more symptoms or conditions,diminishment of the extent of a disease, stabilizing (i.e., notworsening) the state of disease, prevention of a disease's transmissionor spread, delay or slowing of disease progression, amelioration orpalliation of the disease state, diminishment of the reoccurrence ofdisease, and remission, whether partial or total and whether detectableor undetectable. In other words, “treatment” as used herein includes anycure, amelioration, or prevention of a disease. Treatment may preventthe disease from occurring; inhibit the disease's spread; relieve thedisease's symptoms (e.g., symptoms of diabetes, for example includingincreased thirst and urination, fatigue, or blurred vision), fully orpartially remove the disease's underlying cause, shorten a disease'sduration, or do a combination of these things.

“Treating” and “treatment” as used herein include prophylactictreatment. Treatment methods include administering to a subject atherapeutically effective amount of an active agent. The administeringstep may consist of a single administration or may include a series ofadministrations. The length of the treatment period depends on a varietyof factors, such as the severity of the condition, the age of thepatient, the concentration of active agent, the activity of thecompositions used in the treatment, or a combination thereof. It willalso be appreciated that the effective dosage of an agent used for thetreatment or prophylaxis may increase or decrease over the course of aparticular treatment or prophylaxis regime. Changes in dosage may resultand become apparent by standard diagnostic assays known in the art. Insome instances, chronic administration may be required. For example, thecompositions are administered to the subject in an amount and for aduration sufficient to treat the patient. In embodiments, the treatingor treatment is no prophylactic treatment.

The term “prevent” refers to a decrease in the occurrence of a disease(e.g., metabolic disorder) or disease symptoms (e.g.,diabetes-associated disease symptoms) in a patient. As indicated above,the prevention may be complete (no detectable symptoms) or partial, suchthat fewer symptoms are observed than would likely occur absenttreatment. In embodiments, the diabetes-associated disease symptom is asymptom associated with nephropathy, retinopathy, neuropathy,cardiovascular disease, or inflammation.

“Patient” or “subject in need thereof” refers to a living organismsuffering from or prone to a disease or condition that can be treated byadministration of a pharmaceutical composition as provided herein.Non-limiting examples include humans, other mammals, bovines, rats,mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammaliananimals. In some embodiments, a patient is human.

An “effective amount” is an amount sufficient for a compound toaccomplish a stated purpose relative to the absence of the compound(e.g. achieve the effect for which it is administered, treat a disease,reduce enzyme activity, increase enzyme activity, reduce a signalingpathway, or reduce one or more symptoms of a disease or condition). Anexample of an “effective amount” is an amount sufficient to contributeto the treatment, prevention, or reduction of a symptom or symptoms of adisease, which could also be referred to as a “therapeutically effectiveamount.” A “reduction” of a symptom or symptoms (and grammaticalequivalents of this phrase) means decreasing of the severity orfrequency of the symptom(s), or elimination of the symptom(s). A“prophylactically effective amount” of a drug is an amount of a drugthat, when administered to a subject, will have the intendedprophylactic effect, e.g., preventing or delaying the onset (orreoccurrence) of an injury, disease, pathology or condition, or reducingthe likelihood of the onset (or reoccurrence) of an injury, disease,pathology, or condition, or their symptoms. The full prophylactic effectdoes not necessarily occur by administration of one dose, and may occuronly after administration of a series of doses. Thus, a prophylacticallyeffective amount may be administered in one or more administrations. An“activity decreasing amount,” as used herein, refers to an amount ofantagonist required to decrease the activity of an enzyme relative tothe absence of the antagonist. A “function disrupting amount,” as usedherein, refers to the amount of antagonist required to disrupt thefunction of an enzyme or protein relative to the absence of theantagonist. The exact amounts will depend on the purpose of thetreatment, and will be ascertainable by one skilled in the art usingknown techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms(vols. 1-3, 1992); Lloyd, The Art, Science and Technology ofPharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999);and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003,Gennaro, Ed., Lippincott, Williams & Wilkins).

For any compound described herein, the therapeutically effective amountcan be initially determined from cell culture assays. Targetconcentrations will be those concentrations of active compound(s) thatare capable of achieving the methods described herein, as measured usingthe methods described herein or known in the art.

As is well known in the art, therapeutically effective amounts for usein humans can also be determined from animal models. For example, a dosefor humans can be formulated to achieve a concentration that has beenfound to be effective in animals. The dosage in humans can be adjustedby monitoring compounds effectiveness and adjusting the dosage upwardsor downwards, as described above. Adjusting the dose to achieve maximalefficacy in humans based on the methods described above and othermethods is well within the capabilities of the ordinarily skilledartisan.

The term “therapeutically effective amount,” as used herein, refers tothat amount of the therapeutic agent sufficient to ameliorate thedisorder, as described above. For example, for the given parameter, atherapeutically effective amount will show an increase or decrease of atleast 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least100%. Therapeutic efficacy can also be expressed as “-fold” increase ordecrease. For example, a therapeutically effective amount can have atleast a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over acontrol.

Dosages may be varied depending upon the requirements of the patient andthe compound being employed. The dose administered to a patient, in thecontext of the present disclosure, should be sufficient to effect abeneficial therapeutic response in the patient over time. The size ofthe dose also will be determined by the existence, nature, and extent ofany adverse side-effects. Determination of the proper dosage for aparticular situation is within the skill of the practitioner. Generally,treatment is initiated with smaller dosages which are less than theoptimum dose of the compound. Thereafter, the dosage is increased bysmall increments until the optimum effect under circumstances isreached. Dosage amounts and intervals can be adjusted individually toprovide levels of the administered compound effective for the particularclinical indication being treated. This will provide a therapeuticregimen that is commensurate with the severity of the individual'sdisease state.

As used herein, the term “administering” means oral administration,administration as a suppository, topical contact, intravenous,parenteral, intraperitoneal, intramuscular, intralesional, intrathecal,intranasal or subcutaneous administration, or the implantation of aslow-release device, e.g., a mini-osmotic pump, to a subject.Administration is by any route, including parenteral and transmucosal(e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, ortransdermal). Parenteral administration includes, e.g., intravenous,intramuscular, intra-arteriole, intradermal, subcutaneous,intraperitoneal, intraventricular, and intracranial. Other modes ofdelivery include, but are not limited to, the use of liposomalformulations, intravenous infusion, transdermal patches, etc. Inembodiments, the administering does not include administration of anyactive agent other than the recited active agent.

“Co-administer” it is meant that a composition described herein isadministered at the same time, just prior to, or just after theadministration of one or more additional therapies. The compoundsprovided herein can be administered alone or can be coadministered tothe patient. Coadministration is meant to include simultaneous orsequential administration of the compounds individually or incombination (more than one compound). Thus, the preparations can also becombined, when desired, with other active substances (e.g. to reducemetabolic degradation). The compositions of the present disclosure canbe delivered transdermally, by a topical route, or formulated asapplicator sticks, solutions, suspensions, emulsions, gels, creams,ointments, pastes, jellies, paints, powders, and aerosols.

A “cell” as used herein, refers to a cell carrying out metabolic orother function sufficient to preserve or replicate its genomic DNA. Acell can be identified by well-known methods in the art including, forexample, presence of an intact membrane, staining by a particular dye,ability to produce progeny or, in the case of a gamete, ability tocombine with a second gamete to produce a viable offspring. Cells mayinclude prokaryotic and eukaroytic cells. Prokaryotic cells include butare not limited to bacteria. Eukaryotic cells include but are notlimited to yeast cells and cells derived from plants and animals, forexample mammalian, insect (e.g., spodoptera) and human cells. Cells maybe useful when they are naturally nonadherent or have been treated notto adhere to surfaces, for example by trypsinization.

“Control” or “control experiment” is used in accordance with its plainordinary meaning and refers to an experiment in which the subjects orreagents of the experiment are treated as in a parallel experimentexcept for omission of a procedure, reagent, or variable of theexperiment. In some instances, the control is used as a standard ofcomparison in evaluating experimental effects. In some embodiments, acontrol is the measurement of the activity of a protein in the absenceof a compound as described herein (including embodiments and examples).

The terms “bind” and “bound” as used herein is used in accordance withits plain and ordinary meaning and refers to the association betweenatoms or molecules. The association can be direct or indirect. Forexample, bound atoms or molecules may be direct, e.g., by covalent bondor linker (e.g. a first linker or second linker), or indirect, e.g., bynon-covalent bond (e.g. electrostatic interactions (e.g. ionic bond,hydrogen bond, halogen bond), van der Waals interactions (e.g.dipole-dipole, dipole-induced dipole, London dispersion), ring stacking(pi effects), hydrophobic interactions and the like).

The term “thioredoxin activity” as used herein refers to the biologicalactivity of the protein. In embodiments, the thioredoxin activity may beantioxidant activity by facilitating the reduction of other proteins,for example by cysteine thiol-disulfide exchange, at a dithiol-disulfideactive site. The diseases described herein (e.g., metabolic disorder,cardiovascular disease, or inflammatory disease) may be associated withaberrant (e.g., reduced) thioredoxin activity.

The term “thioredoxin interacting protein-thioredoxin protein(TXNIP-TRX) complex” as used herein refers to a thioredoxin proteinbonded (e.g., covalently bonded) to a thioredoxin interacting protein.In embodiments, the TXNIP-TRX complex is detected byco-immunoprecipitation method (e.g., a method in which an antibody toTRX is used to immunoprecipitate it from cells and its association withTXNIP is detected subsequently by Western Blotting with an antibody toTXNIP).

The term “capable of binding” as used herein refers to a moiety (e.g. acompound as described herein) that is able to measurably bind to atarget (e.g., aTXNIP protein or a TXNIP-TRX complex). In embodiments,where a moiety is capable of binding a target, the moiety is capable ofbinding with a Kd of less than about 10 μM, 5 μM, 1 μM, 500 nM, 250 nM,100 nM, 75 nM, 50 nM, 25 nM, 15 nM, 10 nM, 5 nM, 1 nM, or about 0.1 nM.

As used herein, the term “conjugated” when referring to two moietiesmeans the two moieties are bonded, wherein the bond or bonds connectingthe two moieties may be covalent or non-covalent. In embodiments, thetwo moieties are covalently bonded to each other (e.g. directly orthrough a covalently bonded intermediary). In embodiments, the twomoieties are non-covalently bonded (e.g. through ionic bond(s), van derwaal's bond(s)/interactions, hydrogen bond(s), polar bond(s), orcombinations or mixtures thereof).

The terms “metabolic disorder” refers to a disorder characterized by oneor more abnormal metabolic processes in a subject. In embodiments, ametabolic disorder may be associated with, related to, or may bediabetes (e.g., type 1 diabetes or type 2 diabetes), insulin resistance,metabolic syndrome, obesity, hyperlipidemia, hyperglycemia, high serumtriglycerides, and/or high blood pressure. In embodiments, a metabolicdisorder may be associated with, related to, or may be a diabetesassociated disease selected from nephropathy, retinopathy, neuropathy,cardiovascular disease, or inflammation. In embodiments, a metabolicdisorder may be associated with, related to, or may be nephropathy,retinopathy, neuropathy, cardiovascular disease, or inflammation.

A “TXNIP-TRX complex-associated disease” as used herein refers to adisease associated with aberrant TXNIP-TRX complex activity. Inembodiments, the TXNIP-TRX complex-associated disease is a metabolicdisorder, or cardiovascular disease. The diseases described herein(e.g., metabolic disorder, cardiovascular disease, or inflammatorydisease) may be associated with aberrant (e.g., reduced) thioredoxinactivity.

II. Compounds

In an aspect is provided a compound (e.g., a TXNIP-TRX complex inhibitoror a TXNIP expression inhibitor) having the formula:

W¹ is —CR¹═, —N═, or —CH═. W² is —CR²═, —N═, or —CH═. R¹ isindependently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —OCX¹ ₃, —OCH₂X¹, —OCHX¹₂, substituted or unsubstituted alkyl, or substituted or unsubstitutedheteroalkyl. R² is independently halogen, —CX² ₃, —CHX² ₂, —CH₂X², —OCX²₃, —OCH₂X², —OCHX² ₂, substituted or unsubstituted alkyl, or substitutedor unsubstituted heteroalkyl. L³ is a bond, —N(R³)—, —C(O)—,—C(O)N(R³)—, —N(R³)C(O)—, —N(H)—, —C(O)N(H)—, —N(H)C(O)—, —C(O)O—,substituted or unsubstituted alkylene, or substituted or unsubstitutedheteroalkylene. R³ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃,—CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl. R⁶ isindependently hydrogen, halogen, —CX⁶ ₃, —CHX⁶ ₂, —CH₂X⁶, —OCX⁶ ₃,—OCH₂X⁶, —OCHX⁶ ₂, —CN, —SR^(6D), —SOR^(6D), —SO₂R^(6D)—SO₃R^(6D),—SO₄R^(6D), —SONR^(6A)R^(6B), —SO₂NR^(6A)R^(6B),—NR^(6C)C(O)NR^(6A)R^(6B), —N(O), —N(O)₂, —NR^(6A)R^(6B), —C(O)R^(6C),—C(O)—OR^(6C), —C(O)NR^(6A)R^(6B), —OR^(6D), —NR^(6A)SO₂R^(6D),—NR^(6A)C(O)R^(6C), —NR^(6A)C(O)OR^(6C), —NR^(6A)OR^(6C),—NR^(6C)NR^(6A)R^(6B), —C(O)NR^(6C)NR^(6A)R^(6B), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl. R^(6A), R^(6B), R^(6C), and R^(6D) are eachindependently hydrogen, oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl. X¹, X²,and X⁶ are independently —F, —Cl, —Br, or —I.

In embodiments, the compound has the formula:

wherein L³ and R⁶ are as described herein.

In embodiments, the compound has the formula:

wherein L³ and R⁶ are as described herein.

In embodiments, the compound has the formula:

wherein L³ and R⁶ are as described herein.

In embodiments, the compound has the formula:

wherein R¹, R², L³, and R⁶ are as described herein.

In embodiments, the compound has the formula:

wherein R¹, L³, and R⁶ are as described herein.

In embodiments, the compound has the formula:

wherein R², L³, and R⁶ are as described herein.

In embodiments, the compound has the formula:

wherein W¹, W², and R⁶ are as described herein.

In embodiments, the compound has the formula:

wherein R⁶ is as described herein. In embodiments, the compound has theformula:

wherein R⁶ is as described herein. In embodiments, the compound has theformula:

wherein R⁶ is as described herein. In embodiments, the compound has theformula:

wherein R⁶ is as described herein. In embodiments, the compound has theformula:

wherein R⁶ is as described herein.

In embodiments, the compound has the formula:

wherein R³ and R⁶ are as described herein. In embodiments, the compoundhas the formula:

wherein R³ and R⁶ are as described herein. In embodiments, the compoundhas the formula:

wherein R³ and R⁶ are as described herein.In embodiments, the compound has the formula:

wherein R³ and R⁶ are as described herein. In embodiments, the compoundhas the formula:

wherein R⁶ is as described herein.

In embodiments, the compound has the formula:

wherein R³ and R⁶ are as described herein. In embodiments, the compoundhas the formula:

R⁶, wherein R³ and R⁶ are as described herein. In embodiments, thecompound has the formula:

wherein R⁶ is as described herein. In embodiments, the compound has theformula:

R⁶, wherein R⁶ is as described herein. In embodiments, the compound hasthe formula:

wherein R⁶ is as described herein. In embodiments, the compound has theformula:

wherein R⁶ is as described herein. In embodiments, the compound has theformula:

R⁶, wherein R³ and R⁶ are as described herein. In embodiments, thecompound has the formula:

R⁶, wherein R⁶ is as described herein. In embodiments, the compound hasthe formula:

wherein R⁶ is as described herein. In embodiments, the compound has theformula:

wherein R⁶ is as described herein. In embodiments, the compound has theformula:

R⁶ wherein R⁶ is as described herein. In embodiments, the compound hasthe formula:

wherein R¹, R³, and R⁶ are as described herein. In embodiments, thecompound has the formula:

wherein R¹ and R⁶ are as described herein. In embodiments, the compoundhas the formula:

R⁶, wherein R¹, R², R³, and R⁶ are as described herein. In embodiments,the compound has the formula:

wherein R¹, R², and R⁶ are as described herein. In embodiments, thecompound has the formula:

wherein R¹, R², R³, and R⁶ are as described herein. In embodiments, thecompound has the formula:

R⁶, wherein R¹, R², and R⁶ are as described herein. In embodiments, thecompound has the formula

wherein R¹, R², R³ and R⁶ are as described herein.

In embodiments, W¹ is —N═. In embodiments, W¹ is —CH═. In embodiments,W¹ is —CR¹═, wherein R¹ is as described herein. In embodiments, W¹ is—CX¹═, wherein X¹ is a halogen. In embodiments, W¹ is

In embodiments, W² is —N═. In embodiments, W² is —CH═. In embodiments,W² is —CR²═, wherein R² is as described herein. In embodiments, W² is—CX²═, wherein X² is a halogen. In embodiments, W² is

In embodiments, R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹,—OCX¹ ₃, —OCH₂X¹, —OCHX¹ ₂, substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), or substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered. In embodiments, R¹ is independently halogen, —CX¹ ₃,—CHX¹ ₂, —CH₂X¹, —OCX¹ ₃, —OCH₂X¹, —OCHX¹ ₂, substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted alkyl, substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted heteroalkyl. Inembodiments, R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —OCX¹₃, —OCH₂X¹, —OCHX¹ ₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —OCX¹₃, —OCH₂X¹, —OCHX¹ ₂, unsubstituted C₁-C₄ alkyl, or unsubstituted 2 to 4membered heteroalkyl.

In embodiments, a substituted R¹ (e.g., substituted alkyl, substitutedheteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl,substituted aryl, and/or substituted heteroaryl) is substituted with atleast one substituent group, size-limited substituent group, or lowersubstituent group; wherein if the substituted R¹ is substituted with aplurality of groups selected from substituent groups, size-limitedsubstituent groups, and lower substituent groups; each substituentgroup, size-limited substituent group, and/or lower substituent groupmay optionally be different. In embodiments, when R¹ is substituted, itis substituted with at least one substituent group. In embodiments, whenR¹ is substituted, it is substituted with at least one size-limitedsubstituent group. In embodiments, when R¹ is substituted, it issubstituted with at least one lower substituent group.

In embodiments, R¹ is halogen. In embodiments, R¹ is —Cl.

In embodiments, R² is independently halogen, —CX² ₃, —CHX² ₂, —CH₂X²,—OCX² ₃, —OCH₂X², —OCHX² ₂, substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), or substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered. In embodiments, R² is independently halogen, —CX² ₃,—CHX² ₂, —CH₂X², —OCX² ₃, —OCH₂X², —OCHX² ₂, substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted alkyl, substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted heteroalkyl. Inembodiments, R² is independently halogen, —CX² ₃, —CHX² ₂, —CH₂X², —OCX²₃, —OCH₂X², —OCHX² ₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). Inembodiments, R² is independently halogen, —CX² ₃, —CHX² ₂, —CH₂X², —OCX²₃, —OCH₂X², —OCHX² ₂, unsubstituted C₁-C₄ alkyl, or unsubstituted 2 to 4membered heteroalkyl.

In embodiments, a substituted R² (e.g., substituted alkyl, substitutedheteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl,substituted aryl, and/or substituted heteroaryl) is substituted with atleast one substituent group, size-limited substituent group, or lowersubstituent group; wherein if the substituted R² is substituted with aplurality of groups selected from substituent groups, size-limitedsubstituent groups, and lower substituent groups; each substituentgroup, size-limited substituent group, and/or lower substituent groupmay optionally be different. In embodiments, when R² is substituted, itis substituted with at least one substituent group. In embodiments, whenR² is substituted, it is substituted with at least one size-limitedsubstituent group. In embodiments, when R² is substituted, it issubstituted with at least one lower substituent group.

In embodiments, R² is halogen. In embodiments, R² is —Cl.

In embodiments, L³ is a bond, —N(R³)—, —C(O)—, —C(O)N(R³)—, —N(R³)C(O)—,—N(H)—, —C(O)N(H)—, —N(H)C(O)—, —C(O)O—, substituted or unsubstitutedC₁-C₆ alkylene, or substituted or unsubstituted 2 to 6 memberedheteroalkylene. In embodiments, L³ is a bond, —N(R³)—, —C(O)—,—C(O)N(R³)—, —N(R³)C(O)—, —N(H)—, —C(O)N(H)—, —N(H)C(O)—, —C(O)O—,R³-substituted or unsubstituted alkylene (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), or R³-substituted or unsubstituted heteroalkylene (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered). In embodiments, L³ is a bond, —N(R³)—, —C(O)—, —C(O)N(R³)—,—N(R³)C(O)—, —N(H)—, —C(O)N(H)—, —N(H)C(O)—, —C(O)O—, unsubstitutedalkylene (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), or unsubstitutedheteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered,2 to 3 membered, or 4 to 5 membered).

In embodiments, L³ is a bond, —N(R³)—, —C(O)—, —C(O)N(R³)—, —N(R³)C(O)—,—N(H)—, —C(O)N(H)—, —N(H)C(O)—, —C(O)O—, substituted or unsubstitutedC₁-C₆ alkylene, or substituted or unsubstituted 2 to 6 memberedheteroalkylene. In embodiments, L³ is a bond, —N(R³)—, —C(O)—,—C(O)N(R³)—, —N(R³)C(O)—, —N(H)—, —C(O)N(H)—, —N(H)C(O)—, —C(O)O—,R³-substituted or unsubstituted C₁-C₆ alkylene, or R³-substituted orunsubstituted 2 to 6 membered heteroalkylene.

In embodiments, L³ is a bond, —N(R³)—, —C(O)—, —C(O)N(R³)—, —N(R³)C(O)—,—N(H)—, —C(O)N(H)—, —N(H)C(O)—, —C(O)O—, unsubstituted alkylene (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), or unsubstituted heteroalkylene (e.g., 2to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered).

In embodiments, L³ is —N(H)— or R³-substituted or unsubstituted C₁-C₆alkylene. In embodiments, L³ is —N(H)—. In embodiments, L³ isR³-substituted or unsubstituted C₁-C₆ alkylene.

In embodiments, R³ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃,—CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted orunsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered). In embodiments, R³ is independently oxo, halogen, —CCl₃,—CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F,—CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH,—NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,—OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R³ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃,—CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R⁴-substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R⁴-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), R⁴-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),R⁴-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered,3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),R⁴-substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), orR⁴-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

In embodiments, R³ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃,—CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R⁴-substituted or unsubstitutedC₁-C₈ alkyl, R⁴-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R⁴-substituted or unsubstituted C₃-C₅ cycloalkyl,R⁴-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R⁴-substituted or unsubstituted C₆-C₁₀ aryl, or R⁴-substituted orunsubstituted 5 to 10 membered heteroaryl. In embodiments, R³ isindependently oxo. In embodiments, R³ is independently unsubstitutedC₁-C₄ alkyl.

In embodiments, R³ is independently —COOH, —CONH₂, R⁴-substituted orunsubstituted C₁-C₄ alkyl, R⁴-substituted or unsubstituted 2 to 4membered heteroalkyl, R⁴-substituted or unsubstituted C₅-C₆ cycloalkyl,R⁴-substituted or unsubstituted 5 to 6 membered heterocycloalkyl,R⁴-substituted or unsubstituted C₆-C₁₀ aryl, or R⁴-substituted orunsubstituted 5 to 10 membered heteroaryl. In embodiments, R³ isindependently —COOH. In embodiments, R³ is independently unsubstitutedC₁-C₄ alkyl. In embodiments, R³ is unsubstituted methyl. In embodiments,R³ is independently unsubstituted isopropyl. In embodiments, R³ isindependently unsubstituted isobutyl. In embodiments, R³ isindependently unsubstituted n-butyl. In embodiments, R³ is independentlyR⁴-substituted C₁-C₄ alkyl. In embodiments, R³ is independentlyphenyl-substituted C₁ alkyl. In embodiments, R³ is independentlyR⁴-substituted or unsubstituted 2 to 4 membered heteroalkyl. Inembodiments, R³ is independently

In embodiments, R³ is independently —S(O)CH₃. In embodiments, R³ isindependently R⁴-substituted or unsubstituted C₆-C₁₀ aryl. Inembodiments, R³ is independently unsubstituted phenyl. In embodiments,R³ is independently

In embodiments, R³ is independently

In embodiments, R³ is independently

In embodiments, R³ is independently unsubstituted isopropyl.

In embodiments, R³ is independently —COOH, —CONH₂, R⁴-substituted orunsubstituted C₁-C₄ alkyl, R⁴-substituted or unsubstituted 2 to 4membered heteroalkyl, R⁴-substituted or unsubstituted C₅-C₆ cycloalkyl,R⁴-substituted or unsubstituted 5 to 6 membered heterocycloalkyl,R⁴-substituted or unsubstituted C₆-C₁₀ aryl, or R⁴-substituted orunsubstituted 5 to 10 membered heteroaryl. In embodiments, R³ isindependently —COOH. In embodiments, R³ is independently R⁴-substitutedor unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R³ isindependently —S(O)CH₃. In embodiments, R³ is independentlyR⁴-substituted or unsubstituted C₆-C₁₀ aryl. In embodiments, R³ isindependently unsubstituted phenyl. In embodiments, R³ is independently

In embodiments, R³ is independently

In embodiments, R³ is independently

R⁴ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted orunsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered). In embodiments, R⁴ is independently oxo, halogen, —CCl₃,—CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F,—CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH,—NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,—OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R⁴ is independently oxo or halogen. In embodiments, R⁴is independently R⁵-substituted or unsubstituted C₆-C₁₀ aryl. Inembodiments, R⁴ is independently unsubstituted phenyl.

In embodiments, R⁴ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃,—CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R⁵-substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R⁵-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), R⁵-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),R⁵-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered,3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),R⁵-substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), orR⁵-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

In embodiments, R⁴ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃,—CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R⁵-substituted or unsubstitutedC₁-C₈ alkyl, R⁵-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R⁵-substituted or unsubstituted C₃-C₈ cycloalkyl,R⁵-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R⁵-substituted or unsubstituted C₆-C₁₀ aryl, or R⁵-substituted orunsubstituted 5 to 10 membered heteroaryl.

R⁵ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R⁵ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃,—CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted C₁-C₅ alkyl,unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C₃-C₈cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl,unsubstituted C₆-C₁₀ aryl, or unsubstituted 5 to 10 membered heteroaryl.

In embodiments, R⁶ is independently hydrogen, halogen, —CX⁶ ₃, —CHX⁶ ₂,—CH₂X⁶, —OCX⁶ ₃, —OCH₂X⁶, —OCHX⁶ ₂, —CN, —SR^(6D), —SOR^(6D),—SO₂R^(6D), —SO₃R^(6D), —SO₄R^(6D), —SONR^(6A)R^(6B)—SO₂NR^(6A)R^(6B),—NR^(6C)C(O)NR^(6A)R^(6B), —N(O), —N(O)₂, —NR^(6A)R^(6B)—C(O)R^(6C),—C(O)—OR^(6C), —C(O)NR^(6A)R^(6B), —OR^(6D), —NR^(6A)SO₂R^(6D),—NR^(6A)C(O)R^(6C), —NR^(6A)C(O)OR^(6C), —NR^(6A)OR^(6C),—NR^(6C)NR^(6A)R^(6B), —C(O)NR^(6C)NR^(6A)R^(6B), substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substitutedor unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), orsubstituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered).

In embodiments, R⁶ is independently hydrogen, halogen, —CX⁶ ₃, —CHX⁶ ₂,—CH₂X⁶, —OCX⁶ ₃, —OCH₂X⁶, —OCHX⁶ ₂, —CN, —SH, —SOH, —SO₂H, —SO₃H, —SO₄H,—SONHR^(6B), —SO₂NHR^(6B), —NR^(6C)C(O)NHR^(6B), —NHC(O)NR^(6A)R^(6B),—N(O), —N(O)₂, —NHR^(6B), —C(O)H, —C(O)—OH, —C(O)NHR^(6B), —OH,—NHSO₂R^(6D), —NR^(6A)SO₂H, —NR^(6A)C(O)H, —NHC(O)R^(6C),—NHC(O)OR^(6C), —NR^(6A)C(O)OH, —NHOR^(6C), —NR^(6A)OH,—NHNR^(6A)R^(6B), —NR^(6C)NHR^(6B), —NR^(6C)NR^(6A)H,—C(O)NHNR^(6A)R^(6B), —C(O)NR^(6C)NHR^(6B), —C(O)NR^(6C)NR^(6A)H,substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl),or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

In embodiments, R⁶ is independently hydrogen, halogen, —CX⁶ ₃, —CHX⁶ ₂,—CH₂X⁶, —OCX⁶ ₃, —OCH₂X⁶, —OCHX⁶ ₂, —CN, —SR^(6D), —SOR^(6D),—SO₂R^(6D), —SO₃R^(6D), —SO₄R^(6D), —SONR^(6A)R^(6B)—SO₂NR^(6A)R^(6B),—NR^(6C)C(O)NR^(6A)R^(6B), —N(O), —N(O)₂, —NR^(6A)R^(6B)—C(O)R^(6C),—C(O)—OR^(6C), —C(O)NR^(6A)R^(6B), —OR^(6D), —NR^(6A)SO₂R^(6D),—NR^(6A)C(O)R^(6C), —NR^(6A)C(O)OR^(6C), —NR^(6A)OR^(6C),—NR^(6C)NR^(6A)R^(6B), —C(O)NR^(6C)NR^(6A)R^(6B), unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R⁶ is independently —SOR^(6D), —C(O)R^(6C),—C(O)—OR^(6C), —C(O)NR^(6A)R^(6B)—NR^(6A)C(O)R^(6C), or—C(O)NR^(6C)NR^(6A)R^(6B). In embodiments, R⁶ is independently —SOR^(6D)In embodiments, R⁶ is independently —C(O)R^(6C). In embodiments, R⁶ isindependently —C(O)—OR^(6C) In embodiments, R⁶ is independently—C(O)NR^(6A)R^(6B). In embodiments, R⁶ is independently—NR^(6A)C(O)R^(6C). In embodiments, R⁶ is independently—C(O)NR^(6C)NR^(6A)R^(6B) In embodiments, R⁶ is independently—C(O)NHR^(6B). In embodiments, R⁶ is independently —NHC(O)R^(6C). Inembodiments, R⁶ is independently —C(O)NHNHR^(6B).

In embodiments, R⁶ is independently an unsubstituted 3 to 8 memberedheterocycloalkyl. In embodiments, R⁶ is independently an unsubstituted 5to 6 membered heterocycloalkyl. In embodiments, R⁶ is independently anunsubstituted morpholinyl. In embodiments, R⁶ is independently anR⁷-substituted 3 to 8 membered heterocycloalkyl. In embodiments, R⁶ isindependently an R⁷-substituted 5 to 6 membered heterocycloalkyl. Inembodiments, R⁶ is independently

In embodiments R⁷ is independently an R⁸-substituted or unsubstitutedC₆-C₁₀ aryl. In embodiments R⁷ is independently an R⁸-substituted orunsubstituted phenyl. In embodiments R⁷ is independently anR⁸-substituted or unsubstituted C₆-C₁₀ aryl. In embodiments R⁷ isindependently

In embodiments, R⁸ is an unsubstituted 2 to 4 membered heteroalkyl. Inembodiments, R⁸ is an unsubstituted methoxy.

In embodiments, R⁶ is independently —C(O)NR^(6C)NR^(6A)R^(6B). Inembodiments, R^(6C) is independently hydrogen. In embodiments, R^(6A) isindependently hydrogen. In embodiments, R^(6B) is independentlysubstituted C₄-C₈ alkyl. In embodiments, R^(6B) is independentlyR^(7B)-substituted C₄-C₈ alkyl.

In embodiments, R⁶ is independently hydrogen, halogen, —CX⁶ ₃, —CHX⁶ ₂,—CH₂X⁶, —OCX⁶ ₃, —OCH₂X⁶, —OCHX⁶ ₂, —CN, —SR^(6D), —SOR^(6D),—SO₂R^(6D), —SO₃R^(6D), —SO₄R^(6D), —SONR^(6A)R^(6B)—SO₂NR^(6A)R^(6B),—NR^(6C)C(O)NR^(6A)R^(6B), —N(O), —N(O)₂, —NR^(6A)R^(6B)—C(O)R^(6C),—C(O)—OR^(6C), —C(O)NR ^(6A)R^(6B), —OR^(6D), —N^(6A)SO₂R^(6D),—NR^(6A)C(O)OR^(6C), —NR^(6A)OR^(6C), —NR^(6C), —NR^(6A)R^(6B),—C(O)NR^(6C)NR^(6A)R^(6B), R⁷-substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R⁷-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), R⁷-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R⁷-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), R⁷-substituted orunsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or R⁷-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered).

In embodiments, R⁶ is independently hydrogen, halogen, —CX⁶ ₃, —CHX⁶ ₂,—CH₂X⁶, —OCX⁶ ₃, —OCH₂X⁶, —OCHX⁶ ₂, —CN, —SR^(6D), —SOR^(6D),—SO₂R^(6D), —SO₃R^(6D), —SO₄R^(6D), —SONR^(6A)R^(6B)—SO₂NR^(6A)R^(6B),—NR^(6C)C(O)NR^(6A)R^(6B), —N(O), —N(O)₂, —NR^(6A)R^(6B)—C(O)R^(6C),—C(O)—OR^(6C), —C(O)NR ^(6A)R^(6B), —OR^(6D), —N^(6A)SO₂R^(6D),—NR^(6A)C(O)R^(6C), —NR^(6A)C(O)OR^(6C), —NR^(6A)OR^(6C),—NR^(6C)NR^(6A)R^(6B), —C(O)NR^(6C)NR^(6A)R^(6B), R⁷-substituted orunsubstituted C₁-C₈ alkyl, R⁷-substituted or unsubstituted 2 to 8membered heteroalkyl, R⁷-substituted or unsubstituted C₃-C₈ cycloalkyl,R⁷-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R⁷-substituted or unsubstituted C₆-C₁₀ aryl, or R⁷-substituted orunsubstituted 5 to 10 membered heteroaryl.

R⁷ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted orunsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered). In embodiments, R⁷ is independently oxo, halogen, —CCl₃,—CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F,—CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH,—NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,—OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R⁷ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃,—CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R′-substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R⁸-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), R⁸-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),R⁸-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered,3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),R⁸-substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), orR⁸-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

In embodiments, R⁷ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃,—CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R⁸-substituted or unsubstitutedC₁-C₈ alkyl, R⁸-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R⁸-substituted or unsubstituted C₃-C₈ cycloalkyl,R⁸-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R′-substituted or unsubstituted C₆-C₁₀ aryl, or R′-substituted orunsubstituted 5 to 10 membered heteroaryl.

R⁸ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted orunsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered).

In embodiments, R⁸ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃,—CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R⁸ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃,—CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R⁹-substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R⁹-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), R⁹-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),R⁹-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered,3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),R⁹-substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), orR⁹-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to9 membered, or 5 to 6 membered).

R⁹ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R⁸ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃,—CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted C₁-C₅ alkyl,unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C₃-C₈cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl,unsubstituted C₆-C₁₀ aryl, or unsubstituted 5 to 10 membered heteroaryl.

In embodiments, R^(6A) is independently hydrogen, oxo, halogen, —CCl₃,—CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F,—CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH,—NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,—OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substitutedor unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), orsubstituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered). In embodiments, R^(6A) is independentlyhydrogen, oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂,—CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂,—NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃,—OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I,—OCH₂F, —N₃, —SF₅, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^(6A) is independently hydrogen, oxo, halogen, —CCl₃,—CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F,—CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH,—NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,—OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(7A)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(7A)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(7A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(7A)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(7A)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R^(7A)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered).

In embodiments, R^(6A) is independently hydrogen, oxo, halogen, —CCl₃,—CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F,—CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH,—NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,—OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(7A)-substituted orunsubstituted C₁-C₈ alkyl, R^(7A)-substituted or unsubstituted 2 to 8membered heteroalkyl, R^(7A)-substituted or unsubstituted C₃-C₈cycloalkyl, R^(7A)-substituted or unsubstituted 3 to 8 memberedheterocycloalkyl, R^(7A)-substituted or unsubstituted C₆-C₁₀ aryl, orR^(7A)-substituted or unsubstituted 5 to 10 membered heteroaryl.

R^(7A) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted orunsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered).

In embodiments, R^(7A) is independently oxo, halogen, —CCl₃, —CBr₃,—CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^(7A) is independently oxo, halogen, —CCl₃, —CBr₃,—CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SFS, R^(8A)-substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R^(8A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), R^(8A)-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),R^(8A)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), R^(8A)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or R^(9A)-substituted or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^(7A) is independently oxo, halogen, —CCl₃, —CBr₃,—CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(8A)-substituted or unsubstitutedC₁-C₈ alkyl, R^(8A)-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R^(8A)-substituted or unsubstituted C₃-C₈ cycloalkyl,R^(8A)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R^(8A)-substituted or unsubstituted C₆-C₁₀ aryl, or R^(8A)-substitutedor unsubstituted 5 to 10 membered heteroaryl.

R^(8A) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted orunsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered).

In embodiments, R^(8A) is independently oxo, halogen, —CCl₃, —CBr₃,—CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^(8A) is independently oxo, halogen, —CCl₃, —CBr₃,—CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted C₁-C₈ alkyl,unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C₃-C₈cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl,unsubstituted C₆-C₁₀ aryl, or unsubstituted 5 to 10 membered heteroaryl.

In embodiments, R^(8A) is independently oxo, halogen, —CCl₃, —CBr₃,—CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(9A)-substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R^(9A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), R^(9A)-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),R^(9A)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), R^(9A)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or R^(9A)-substituted or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered).

R^(9A) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^(6B) is independently hydrogen, oxo, halogen, —CCl₃,—CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F,—CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH,—NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,—OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substitutedor unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), orsubstituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered). In embodiments, R^(6B) is independentlyhydrogen, oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂, —CHBr₂, —CHF₂,—CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂,—NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃,—OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I,—OCH₂F, —N₃, —SF₅, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^(6B) is independently hydrogen, oxo, halogen, —CCl₃,—CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F,—CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH,—NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,—OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(7B)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(7B)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(7B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(7B)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(7B)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R^(7B)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered).

In embodiments, R^(6B) is independently hydrogen, oxo, halogen, —CCl₃,—CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F,—CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH,—NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,—OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(7B)-substituted orunsubstituted C₁-C₈ alkyl, R^(7B)-substituted or unsubstituted 2 to 8membered heteroalkyl, R^(7B)-substituted or unsubstituted C₃-C₈cycloalkyl, R^(7B)-substituted or unsubstituted 3 to 8 memberedheterocycloalkyl, R^(7B)-substituted or unsubstituted C₆-C₁₀ aryl, orR^(7B)-substituted or unsubstituted 5 to 10 membered heteroaryl.

In embodiments, R^(6B) is R^(7B)-substituted or unsubstituted C₁-C₆alkyl, R^(7B)-substituted or unsubstituted phenyl, or R^(7B)-substitutedor unsubstituted 5 to 6 membered heteroaryl. In embodiments, R^(6B) isR^(7B)-substituted or unsubstituted C₁-C₆ alkyl. In embodiments, R^(6B)is R^(7B)-substituted or unsubstituted phenyl. In embodiments, R^(6B) isR^(7B)-substituted or unsubstituted 5 to 6 membered heteroaryl. Inembodiments, R^(6B) is R^(7B)-substituted C₁-C₆ alkyl. In embodiments,R^(6B) is R^(7B)-substituted phenyl. In embodiments, R^(6B) isR^(7B)-substituted 5 to 6 membered heteroaryl. In embodiments, R^(6B) isunsubstituted C₁-C₆ alkyl. In embodiments, R^(6B) is unsubstitutedphenyl. In embodiments, R^(6B) is unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, R^(6B) is independently R^(7B)-substituted orunsubstituted C₁-C₆ alkyl, R^(7B)-substituted or unsubstituted phenyl,or R^(7B)-substituted or unsubstituted 5 to 6 membered heteroaryl. Inembodiments, R^(6B) is independently R^(7B)-substituted or unsubstitutedC₁-C₆ alkyl. In embodiments, R^(6B) is independently R^(7B)-substitutedor unsubstituted phenyl. In embodiments, R^(6B) is independentlyR^(7B)-substituted or unsubstituted 5 to 6 membered heteroaryl. Inembodiments, R^(6B) is independently R^(7B)-substituted C₁-C₆ alkyl. Inembodiments, R^(6B) is independently R^(7B)-substituted phenyl. Inembodiments, R^(6B) is independently R^(7B)-substituted 5 to 6 memberedheteroaryl. In embodiments, R^(6B) is independently unsubstituted C₁-C₆alkyl. In embodiments, R^(6B) is independently unsubstituted phenyl. Inembodiments, R^(6B) is independently unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, R^(6B) is R^(7B)-substituted C₁-C₆ alkyl,R^(7B)-substituted phenyl, or R^(7B)-substituted pyridyl. Inembodiments, R^(6B) is R^(7B)-substituted C₁-C₆ alkyl. In embodiments,R^(6B) is R^(7B)-substituted phenyl. In embodiments, R^(6B) isR^(7B)-substituted pyridyl.

In embodiments, R^(6B) is independently R^(7B)-substituted C₁-C₆ alkyl,R^(7B)-substituted phenyl, or R^(7B)-substituted pyridyl. Inembodiments, R^(6B) is independently R^(7B)-substituted C₁-C₆ alkyl. Inembodiments, R^(6B) is independently R^(7B)-substituted phenyl. Inembodiments, R^(6B) is independently R^(7B)-substituted pyridyl.

In embodiments, R^(6B) is oxo-substituted C₁-C₆ alkyl.

In embodiments, R^(6B) is independently oxo-substituted C₁-C₆ alkyl.

R^(7B) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted orunsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered).

In embodiments, R^(7B) is independently oxo, halogen, —CCl₃, —CBr₃,—CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^(7B) is halogen, unsubstituted C₁-C₃ alkyl,R^(8B)-substituted or unsubstituted 2 to 4 membered heteroalkyl, orunsubstituted C₆-C₁₀ aryl. In embodiments, R^(7B) is halogen. Inembodiments, R^(7B) is unsubstituted C₁-C₃ alkyl. In embodiments, R^(7B)is R^(8B)-substituted or unsubstituted 2 to 4 membered heteroalkyl. Inembodiments, R^(7B) is R^(8B)-substituted 2 to 4 membered heteroalkyl.In embodiments, R^(7B) is unsubstituted 2 to 4 membered heteroalkyl. Inembodiments, R^(7B) is unsubstituted C₆-C₁₀ aryl. In embodiments, R^(7B)is unsubstituted C₆ aryl.

In embodiments, R^(7B) is independently halogen, unsubstituted C₁-C₃alkyl, R^(8B)-substituted or unsubstituted 2 to 4 membered heteroalkyl,or unsubstituted C₆-C₁₀ aryl. In embodiments, R^(7B) is independentlyhalogen. In embodiments, R^(7B) is independently unsubstituted C₁-C₃alkyl. In embodiments, R^(7B) is independently R^(8B)-substituted orunsubstituted 2 to 4 membered heteroalkyl. In embodiments, R^(7B) isindependently R^(8B)-substituted 2 to 4 membered heteroalkyl. Inembodiments, R^(7B) is independently unsubstituted 2 to 4 memberedheteroalkyl. In embodiments, R^(7B) is independently unsubstitutedC₆-C₁₀ aryl. In embodiments, R^(7B) is independently unsubstituted C₆aryl.

In embodiments, R^(7B) is —Cl, —Br, unsubstituted methyl, unsubstitutedethyl, unsubstituted isopropyl, unsubstituted methoxy,R^(8B)-substituted 3 to 4 membered heteroalkyl, or unsubstituted phenyl.In embodiments, R^(7B) is —Cl. In embodiments, R^(7B) is —Br. Inembodiments, R^(7B) is unsubstituted methyl. In embodiments, R^(7B) isunsubstituted ethyl. In embodiments, R^(7B) is unsubstituted isopropyl.In embodiments, R^(7B) is unsubstituted methoxy. In embodiments, R^(7B)is R^(8B)-substituted 3 to 4 membered heteroalkyl. In embodiments,R^(7B) is unsubstituted phenyl.

In embodiments, R^(8B) is independently —Cl, —Br, unsubstituted methyl,unsubstituted ethyl, unsubstituted isopropyl, unsubstituted methoxy,R^(8B)-substituted 3 to 4 membered heteroalkyl, or unsubstituted phenyl.In embodiments, R^(7B) is independently —Cl. In embodiments, R^(7B) isindependently —Br. In embodiments, R^(7B) is independently unsubstitutedmethyl. In embodiments, R^(7B) is independently unsubstituted ethyl. Inembodiments, R^(7B) is independently unsubstituted isopropyl. Inembodiments, R^(7B) is independently unsubstituted methoxy. Inembodiments, R^(7B) is independently R^(8B)-substituted 3 to 4 memberedheteroalkyl. In embodiments, R^(7B) is independently unsubstitutedphenyl.

In embodiments, R^(7B) is independently oxo, R^(8B)-substituted orunsubstituted C₆-C₁₀ aryl, or unsubstituted 5 to 10 membered heteroaryl.In embodiments, R^(7B) is independently oxo. In embodiments, R^(7B) isindependently R^(8B)-substituted or unsubstituted C₆-C₁₀ aryl. Inembodiments, R^(7B) is independently R^(8B)-substituted C₆-C₁₀ aryl. Inembodiments, R^(7B) is independently unsubstituted C₆-C₁₀ aryl. Inembodiments, R^(7B) is independently R^(8B)-substituted C₆ aryl. Inembodiments, R^(7B) is independently unsubstituted C₆ aryl. Inembodiments, R^(7B) is independently unsubstituted 5 to 10 memberedheteroaryl. In embodiments, R^(7B) is independently unsubstituted 5 to 6membered heteroaryl. In embodiments, R^(7B) is independentlyunsubstituted 6 membered heteroaryl. In embodiments, R^(7B) isindependently unsubstituted pyridyl.

In embodiments, R^(7B) is independently oxo,

or unsubstituted pyridyl. In embodiments, R^(7B) is independently oxo.In embodiments, R^(7B) is independently

wherein each instance of R^(8B) is independent and as described herein.In embodiments, R^(7B) is independently

In embodiments, R^(7B) is independently unsubstituted pyridyl.

In embodiments, R^(7B) is independently oxo, halogen, —CCl₃, —CBr₃,—CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(8B)-substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R^(8B)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), R^(8B)-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),R^(8B)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), R^(8B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or R^(8B)-substituted or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^(7B) is independently oxo, halogen, —CCl₃, —CBr₃,—CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SFS, R^(8B)-substituted or unsubstitutedC₁-C₈ alkyl, R^(8B)-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R^(8B)-substituted or unsubstituted C₃-C₈ cycloalkyl,R^(8B)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R^(8B)-substituted or unsubstituted C₆-C₁₀ aryl, or R^(8B)-substitutedor unsubstituted 5 to 10 membered heteroaryl.

R^(8B) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted orunsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered).

In embodiments, R^(8B) is independently oxo, halogen, —CCl₃, —CBr₃,—CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^(8B) is independently oxo, halogen, —CCl₃, —CBr₃,—CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SFS, unsubstituted C₁-C₈ alkyl,unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C₃-C₈cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl,unsubstituted C₆-C₁₀ aryl, or unsubstituted 5 to 10 membered heteroaryl.

In embodiments, R^(8B) is oxo. In embodiments, R^(8B) is halogen.

In embodiments, R^(8B) is independently oxo. In embodiments, R^(8B) isindependently halogen.

In embodiments, R^(8B) is independently oxo, halogen, —CCl₃, —CBr₃,—CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(9B)-substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R^(9B)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), R^(9B)-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),R^(9B)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), R^(9B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or R^(9B)-substituted or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered).

R^(9B) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^(6C) is independently hydrogen, oxo, halogen, —CCl₃,—CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F,—CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH,—NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,—OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substitutedor unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), orsubstituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered). In embodiments, R^(6C) is independentlyhydrogen, oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂,—CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂,—NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃,—OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I,—OCH₂F, —N₃, —SF₅, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^(6C) is R^(7C)-substituted or unsubstituted C₆-C₁₀aryl or unsubstituted 5 to 10 membered heteroaryl. In embodiments,R^(6C) is R^(7C)-substituted C₆-C₁₀ aryl. In embodiments, R^(6C) isunsubstituted C₆-C₁₀ aryl or unsubstituted 5 to 10 membered heteroaryl.In embodiments, R^(6C) is unsubstituted 5 to 10 membered heteroaryl. Inembodiments, R^(6C) is unsubstituted 5 to 6 membered heteroaryl. Inembodiments, R^(6C) is unsubstituted 6 membered heteroaryl.

In embodiments, R^(6C) is independently R^(7C)-substituted orunsubstituted C₆-C₁₀ aryl or unsubstituted 5 to 10 membered heteroaryl.In embodiments, R^(6C) is independently R^(7C)-substituted C₆-C₁₀ aryl.In embodiments, R^(6C) is independently unsubstituted C₆-C₁₀ aryl orunsubstituted 5 to 10 membered heteroaryl. In embodiments, R^(6C) isindependently unsubstituted 5 to 10 membered heteroaryl. In embodiments,R^(6C) is independently unsubstituted 5 to 6 membered heteroaryl. Inembodiments, R^(6C) is independently unsubstituted 6 memberedheteroaryl.

In embodiments, R^(6C) is R^(7C)-substituted or unsubstituted phenyl orunsubstituted pyridyl. In embodiments, R^(6C) is R^(7C)-substitutedphenyl. In embodiments, R^(6C) is unsubstituted phenyl. In embodiments,R^(6C) is unsubstituted pyridyl.

In embodiments, R^(6C) is independently R^(7C)-substituted orunsubstituted phenyl or unsubstituted pyridyl. In embodiments, R^(6C) isindependently R^(7C)-substituted phenyl. In embodiments, R^(6C) isindependently unsubstituted phenyl. In embodiments, R^(6C) isindependently unsubstituted pyridyl.

In embodiments, R^(6C) is independently hydrogen, oxo, halogen, —CCl₃,—CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F,—CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH,—NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,—OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(7C)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(7C)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(7C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(7C)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(7C)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R^(7C)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered).

In embodiments, R^(6C) is independently hydrogen, oxo, halogen, —CCl₃,—CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F,—CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH,—NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,—OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SFS, R^(7C)-substituted orunsubstituted C₁-C₈ alkyl, R^(7C)-substituted or unsubstituted 2 to 8membered heteroalkyl, R^(7C)-substituted or unsubstituted C₃-C₈cycloalkyl, R^(7C)-substituted or unsubstituted 3 to 8 memberedheterocycloalkyl, R^(7C)-substituted or unsubstituted C₆-C₁₀ aryl, orR^(7C)-substituted or unsubstituted 5 to 10 membered heteroaryl.

In embodiments, R^(6C) is R^(7C)-substituted or unsubstituted 7 memberedheterocycloalkyl. In embodiments, R^(6C) is R^(7C)-substituted orunsubstituted 6 membered heterocycloalkyl. In embodiments, R^(6C) isR^(7C)-substituted or unsubstituted 5 membered heterocycloalkyl. Inembodiments, R^(6C) is R^(7C)-substituted 7 membered heterocycloalkyl.In embodiments, R^(6C) is R^(7C)-substituted 6 memberedheterocycloalkyl. In embodiments, R^(6C) is R^(7C)-substituted 5membered heterocycloalkyl. In embodiments, R^(6C) is an unsubstituted 7membered heterocycloalkyl. In embodiments, R^(6C) is an unsubstituted 6membered heterocycloalkyl. In embodiments, R^(6C) is an unsubstituted 5membered heterocycloalkyl.

In embodiments, R^(6C) is independently R^(7C)-substituted orunsubstituted 7 membered heterocycloalkyl. In embodiments, R^(6C) isindependently R^(7C)-substituted or unsubstituted 6 memberedheterocycloalkyl. In embodiments, R^(6C) is independentlyR^(7C)-substituted or unsubstituted 5 membered heterocycloalkyl. Inembodiments, R^(6C) is independently R^(7C)-substituted 7 memberedheterocycloalkyl. In embodiments, R^(6C) is independentlyR^(7C)-substituted 6 membered heterocycloalkyl. In embodiments, R^(6C)is independently R^(7C)-substituted 5 membered heterocycloalkyl. Inembodiments, R^(6C) is independently an unsubstituted 7 memberedheterocycloalkyl. In embodiments, R^(6C) is independently anunsubstituted 6 membered heterocycloalkyl. In embodiments, R^(6C) isindependently an unsubstituted 5 membered heterocycloalkyl.

In embodiments, R^(6C) is R^(7C)-substituted piperazinyl,R^(7C)-substituted piperidinyl, or unsubstituted morpholinyl. Inembodiments, R^(6C) is R^(7C)-substituted piperazinyl. In embodiments,R^(6C) is R^(7C)-substituted piperidinyl. In embodiments, R^(6C) isunsubstituted morpholinyl.

In embodiments, R^(6C) is independently R^(7C)-substituted piperazinyl,R^(7C)-substituted piperidinyl, or unsubstituted morpholinyl. Inembodiments, R^(6C) is independently R^(7C)-substituted piperazinyl. Inembodiments, R^(6C) is independently R^(7C)-substituted piperidinyl. Inembodiments, R^(6C) is independently unsubstituted morpholinyl.

In embodiments, R^(6C) is hydrogen, R^(7C)-substituted or unsubstitutedC₁-C₈ alkyl or R^(7C)-substituted or unsubstituted C₆-C₁₀ aryl. Inembodiments, R^(6C) is hydrogen. In embodiments, R^(6C) isR^(7C)-substituted or unsubstituted C₁-C₈ alkyl. In embodiments, R^(6C)is R^(7C)-substituted or unsubstituted C₆-C₁₀ aryl. In embodiments,R^(6C) is unsubstituted C₁-C₈ alkyl. In embodiments, R^(6C) isunsubstituted C₆-C₁₀ aryl. In embodiments, R^(6C) is R^(7C)-substitutedC₁-C₈ alkyl. In embodiments, R^(6C) is R^(7C)-substituted C₆-C₁₀ aryl.

In embodiments, R^(6C) is independently hydrogen, R^(7C)-substituted orunsubstituted C₁-C₈ alkyl or R^(7C)-substituted or unsubstituted C₆-C₁₀aryl. In embodiments, R^(6C) is independently hydrogen. In embodiments,R^(6C) is independently R^(7C)-substituted or unsubstituted C₁-C₈ alkyl.In embodiments, R^(6C) is independently R^(7C)-substituted orunsubstituted C₆-C₁₀ aryl. In embodiments, R^(6C) is independentlyunsubstituted C₁-C₈ alkyl. In embodiments, R^(6C) is independentlyunsubstituted C₆-C₁₀ aryl. In embodiments, R^(6C) is independentlyR^(7C)-substituted C₁-C₈ alkyl. In embodiments, R^(6C) is independentlyR^(7C)-substituted C₆-C₁₀ aryl.

In embodiments, R^(6C) is hydrogen, R^(7C)-substituted or unsubstitutedethyl or R^(7C)-substituted or unsubstituted phenyl. In embodiments,R^(6C) is R^(7C)-substituted or unsubstituted ethyl. In embodiments,R^(6C) is R^(7C)-substituted or unsubstituted phenyl. In embodiments,R^(6C) is R^(7C)-substituted ethyl. In embodiments, R^(6C) isR^(7C)-substituted phenyl. In embodiments, R^(6C) is unsubstitutedethyl. In embodiments, R^(6C) is unsubstituted phenyl.

In embodiments, R^(6C) is independently hydrogen, R^(7C)-substituted orunsubstituted ethyl or R^(7C)-substituted or unsubstituted phenyl. Inembodiments, R^(6C) is independently R^(7C)-substituted or unsubstitutedethyl. In embodiments, R^(6C) is independently R^(7C)-substituted orunsubstituted phenyl. In embodiments, R^(6C) is R^(7C)-substitutedethyl. In embodiments, R^(6C) is independently R^(7C)-substitutedphenyl. In embodiments, R^(6C) is independently unsubstituted ethyl. Inembodiments, R^(6C) is independently unsubstituted phenyl.

R^(7C) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, —NHR^(8C), substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substitutedor unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), orsubstituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered).

In embodiments, R^(7C) is independently oxo, halogen, —CCl₃, —CBr₃,—CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂CI,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, —NHR^(8C), unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^(7C) is oxo, R^(8C)-substituted or unsubstituted C₁-C₂alkyl, unsubstituted 2 to 3 membered heteroalkyl, or R^(8C)-substitutedor unsubstituted C₆-C₁₀ aryl. In embodiments, R^(7C) is oxo. Inembodiments, R^(7C) is R^(8C)-substituted or unsubstituted C₁-C₂ alkyl.In embodiments, R^(7C) is unsubstituted 2 to 3 membered heteroalkyl. Inembodiments, R^(7C) is R^(8C)-substituted or unsubstituted C₆-C₁₀ aryl.In embodiments, R^(7C) is R^(8C)-substituted C₁-C₂ alkyl. Inembodiments, R^(7C) is unsubstituted 3 membered heteroalkyl. Inembodiments, R^(7C) is R^(8C)-substituted C₆-C₁₀ aryl. In embodiments,R^(7C) is R^(8C)-substituted C₆ aryl. In embodiments, R^(7C) is anunsubstituted C₆ aryl. In embodiments, R^(7C) is an unsubstituted C₁-C₂alkyl. In embodiments, R^(7C) is unsubstituted 2 membered heteroalkyl.In embodiments, R^(7C) is an unsubstituted C₆-C₁₀ aryl.

In embodiments, R^(7C) is independently oxo, R^(8C)-substituted orunsubstituted C₁-C₂ alkyl, unsubstituted 2 to 3 membered heteroalkyl, orR^(8C)-substituted or unsubstituted C₆-C₁₀ aryl. In embodiments, R^(7C)is independently oxo. In embodiments, R^(7C) is independentlyR^(8C)-substituted or unsubstituted C₁-C₂ alkyl. In embodiments, R^(7C)is independently unsubstituted 2 to 3 membered heteroalkyl. Inembodiments, R^(7C) is independently R^(8C)-substituted or unsubstitutedC₆-C₁₀ aryl. In embodiments, R^(7C) is independently R^(8C)-substitutedC₁-C₂ alkyl. In embodiments, R^(7C) is independently unsubstituted 3membered heteroalkyl. In embodiments, R^(7C) is independentlyR^(8C)-substituted C₆-C₁₀ aryl. In embodiments, R^(7C) is independentlyR^(8C)-substituted C₆ aryl. In embodiments, R^(7C) is independently anunsubstituted C₆ aryl. In embodiments, R^(7C) is independently anunsubstituted C₁-C₂ alkyl. In embodiments, R^(7C) is independentlyunsubstituted 2 membered heteroalkyl. In embodiments, R^(7C) isindependently an unsubstituted C₆-C₁₀ aryl.

In embodiments, R^(7C) is independently oxo, halogen, —CCl₃, —CBr₃,—CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, —NHR^(8C), R^(8C)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(8C)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(8C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(8C)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(8C)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R^(8C)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered).

In embodiments, R^(7C) is independently oxo, halogen, —CCl₃, —CBr₃,—CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SFS, —NHR^(8C), R^(8C)-substituted orunsubstituted C₁-C₈ alkyl, R^(8C)-substituted or unsubstituted 2 to 8membered heteroalkyl, R^(8C)-substituted or unsubstituted C₃-C₈cycloalkyl, R^(8C)-substituted or unsubstituted 3 to 8 memberedheterocycloalkyl, R^(8C)-substituted or unsubstituted C₆-C₁₀ aryl, orR^(8C)-substituted or unsubstituted 5 to 10 membered heteroaryl.

In embodiments, R^(7C) is —NHR^(8C) or R^(8C)-substituted phenyl. Inembodiments, R^(7C) is —NHR^(8C). In embodiments, R^(7C) isR^(8C)-substituted phenyl.

In embodiments, R^(7C) is independently —NHR^(8C) or R^(8C)-substitutedphenyl. In embodiments, R^(7C) is independently —NHR^(8C). Inembodiments, R^(7C) is independently R^(8C)-substituted phenyl.

In embodiments, R^(7C) is R^(8C)-substituted C₁-C₆ alkyl. Inembodiments, R^(7C) is R^(8C)-substituted C₁-C₄ alkyl. In embodiments,R^(7C) is oxo-substituted C₁-C₆ alkyl.

In embodiments, R^(7C) is independently R^(7C)-substituted C₁-C₆ alkyl.In embodiments, R^(7C) is independently R^(8C)-substituted C₁-C₄ alkyl.In embodiments, R^(7C) is independently oxo-substituted C₁-C₆ alkyl.

R^(8C) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted orunsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered).

In embodiments, R^(8C) is independently oxo, halogen, —CCl₃, —CBr₃,—CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^(8C) is oxo, halogen, unsubstituted C₁-C₄ alkyl, orunsubstituted phenyl. In embodiments, R^(8C) is oxo. In embodiments,R^(8C) is halogen. In embodiments, R^(8C) is unsubstituted C₁-C₄ alkyl.In embodiments, R^(8C) is unsubstituted phenyl. In embodiments, R^(8C)is oxo, —Cl, —Br, unsubstituted methyl, or unsubstituted phenyl. Inembodiments, R^(8C) is —Cl. In embodiments, R^(8C) is —Br. Inembodiments, R^(8C) is unsubstituted methyl. In embodiments, R^(8C) isunsubstituted phenyl.

In embodiments, R^(8C) is independently oxo, halogen, unsubstitutedC₁-C₄ alkyl, or unsubstituted phenyl. In embodiments, R^(8C) isindependently oxo. In embodiments, R^(8C) is independently halogen. Inembodiments, R^(8C) is independently unsubstituted C₁-C₄ alkyl. Inembodiments, R^(8C) is independently unsubstituted phenyl. Inembodiments, R^(8C) is independently oxo, —Cl, —Br, unsubstitutedmethyl, or unsubstituted phenyl. In embodiments, R^(8C) is independently—Cl. In embodiments, R^(8C) is independently —Br. In embodiments, R^(8C)is independently unsubstituted methyl. In embodiments, R^(8C) isindependently unsubstituted phenyl.

In embodiments, R^(8C) is unsubstituted C₁-C₄ alkyl, unsubstituted 2 to4 membered heteroalkyl, unsubstituted C₅-C₆ cycloalkyl, unsubstituted 5to 6 membered heterocycloalkyl, R^(9C)-substituted or unsubstitutedphenyl, or unsubstituted 5 to 6 membered heteroaryl. In embodiments,R^(8C) is unsubstituted C₁-C₄ alkyl. In embodiments, R^(8C) isunsubstituted 2 to 4 membered heteroalkyl. In embodiments, R^(8C) isunsubstituted C₅-C₆ cycloalkyl. In embodiments, R^(8C) is unsubstituted5 to 6 membered heterocycloalkyl. In embodiments, R^(8C) isR^(9C)-substituted or unsubstituted phenyl. In embodiments, R^(8C) isR^(9C)-substituted phenyl. In embodiments, R^(8C) is an unsubstitutedphenyl. In embodiments, R^(8C) is unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, R^(8C) is independently unsubstituted C₁-C₄ alkyl,unsubstituted 2 to 4 membered heteroalkyl, unsubstituted C₅-C₆cycloalkyl, unsubstituted 5 to 6 membered heterocycloalkyl,R^(9C)-substituted or unsubstituted phenyl, or unsubstituted 5 to 6membered heteroaryl. In embodiments, R^(8C) is independentlyunsubstituted C₁-C₄ alkyl. In embodiments, R^(8C) is independentlyunsubstituted 2 to 4 membered heteroalkyl. In embodiments, R^(8C) isindependently unsubstituted C₅-C₆ cycloalkyl. In embodiments, R^(8C) isindependently unsubstituted 5 to 6 membered heterocycloalkyl. Inembodiments, R^(8C) is independently R^(9C)-substituted or unsubstitutedphenyl. In embodiments, R^(8C) is independently R^(9C)-substitutedphenyl. In embodiments, R^(8C) is independently an unsubstituted phenyl.In embodiments, R^(8C) is independently unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, R^(8C) is unsubstituted methoxy or R^(9C)-substitutedphenyl; and R^(9C) is unsubstituted isopropyl. In embodiments, R^(8C) isunsubstituted ethoxy. In embodiments, R^(8C) is unsubstituted methoxy.In embodiments, R^(8C) is R^(9C)-substituted phenyl, wherein R^(9C) isunsubstituted C₁-C₆ alkyl. In embodiments, R^(8C) is R^(9C)-substitutedphenyl, wherein R^(9C) is unsubstituted isopropyl.

In embodiments, R^(8C) is independently unsubstituted methoxy orR^(9C)-substituted phenyl; and R^(9C) is unsubstituted isopropyl. Inembodiments, R^(8C) is independently unsubstituted ethoxy. Inembodiments, R^(8C) is independently unsubstituted methoxy. Inembodiments, R^(8C) is independently R^(9C)-substituted phenyl, whereinR^(9C) is independently unsubstituted C₁-C₆ alkyl. In embodiments,R^(8C) is independently R^(9C)-substituted phenyl, wherein R^(9C) isindependently unsubstituted isopropyl.

In embodiments, R^(8C) is independently oxo, halogen, —CCl₃, —CBr₃,—CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(9C)-substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R^(9C)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), R^(9C)-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),R^(9C)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), R^(9C)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or R^(9C)-substituted or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^(8C) is independently oxo, halogen, —CCl₃, —CBr₃,—CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SFS, R^(9C)-substituted or unsubstitutedC₁-C₈ alkyl, R^(9C)-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R^(9C)-substituted or unsubstituted C₃-C₈ cycloalkyl,R^(9C)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R^(9C)-substituted or unsubstituted C₆-C₁₀ aryl, or R^(9C)-substitutedor unsubstituted 5 to 10 membered heteroaryl.

R^(9C) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^(9C) is independently oxo, halogen, —CCl₃, —CBr₃,—CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted C₁-C₈ alkyl,unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C₃-C₈cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl,unsubstituted C₆-C₁₀ aryl, or unsubstituted 5 to 10 membered heteroaryl.

In embodiments, R^(6D) is independently hydrogen, oxo, halogen, —CCl₃,—CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F,—CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH,—NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,—OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SFS, substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substitutedor unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), orsubstituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered). In embodiments, R⁶¹ is independentlyhydrogen, oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂, —CHBr₂, —CHF₂,—CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂,—NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃,—OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I,—OCH₂F, —N₃, —SF₅, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^(6D) is independently hydrogen, oxo, halogen, —CCl₃,—CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F,—CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH,—NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,—OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(7D)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(7D)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),R^(7D)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(7D)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(7D)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R^(7D)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered).

In embodiments, R^(6D) is independently hydrogen, oxo, halogen, —CCl₃,—CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F,—CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH,—NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,—OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SFS, R^(7D)-substituted orunsubstituted C₁-C₈ alkyl, R^(7D)-substituted or unsubstituted 2 to 8membered heteroalkyl, R^(7D)-substituted or unsubstituted C₃-C₈cycloalkyl, R^(7D)-substituted or unsubstituted 3 to 8 memberedheterocycloalkyl, R^(7D)-substituted or unsubstituted C₆-C₁₀ aryl, orR^(7D)-substituted or unsubstituted 5 to 10 membered heteroaryl.

In embodiments, R^(6D) is R^(7D)-substituted or unsubstituted C₁-C₄alkyl. In embodiments, R^(6D) is R^(7D)-substituted C₁-C₄ alkyl. Inembodiments, R^(6D) is unsubstituted C₁-C₄ alkyl. In embodiments, R^(6D)is unsubstituted methyl.

In embodiments, R^(6D) is independently R^(7D)-substituted orunsubstituted C₁-C₄ alkyl. In embodiments, R^(6D) is independentlyR^(7D)-substituted C₁-C₄ alkyl. In embodiments, R^(6D) is independentlyunsubstituted C₁-C₄ alkyl. In embodiments, R^(6D) is independentlyunsubstituted methyl.

R^(7D) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted orunsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered).

In embodiments, R^(7D) is independently oxo, halogen, —CCl₃, —CBr₃,—CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^(7D) is independently oxo, halogen, —CCl₃, —CBr₃,—CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(8D)-substituted or unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R^(8D)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), R^(8D)-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),R^(8D)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), R^(8D)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or R^(8D)-substituted or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^(7D) is independently oxo, halogen, —CCl₃, —CBr₃,—CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SFS, R^(8D)-substituted or unsubstitutedC₁-C₈ alkyl, R^(8D)-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R^(8D)-substituted or unsubstituted C₃-C₈ cycloalkyl,R^(8D)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R^(8D)-substituted or unsubstituted C₆-C₁₀ aryl, or R^(8D)-substitutedor unsubstituted 5 to 10 membered heteroaryl.

R^(8D) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted orunsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered).

In embodiments, R^(8D) is independently oxo, halogen, —CCl₃, —CBr₃,—CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^(8D) is independently oxo, halogen, —CCl₃, —CBr₃,—CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SFS, unsubstituted C₁-C₈ alkyl,unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C₃-C₈cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl,unsubstituted C₆-C₁₀ aryl, or unsubstituted 5 to 10 membered heteroaryl.

In embodiments, R^(8D) is independently oxo, halogen, —CCl₃, —CBr₃,—CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SFS, R^(9D)-substituted or unsubstitutedalkyl (e.g., C₁-C₅, C₁-C₆, C₁-C₄, or C₁-C₂), R″-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), R^(9D)-substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),R^(9D)-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), R^(9D)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or R^(9D)-substituted or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered).

R^(9D) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, X¹ is —F. In embodiments, X¹ is —Cl. In embodiments, X¹is —Br. In embodiments, X¹ is —I. In embodiments, X² is —F. Inembodiments, X² is —Cl. In embodiments, X² is —Br. In embodiments, X² is—I. In embodiments, X⁶ is —F. In embodiments, X⁶ is —Cl. In embodiments,X⁶ is —Br. In embodiments, X⁶ is —I.

In embodiments, X¹ is independently —F. In embodiments, X¹ isindependently —Cl. In embodiments, X¹ is independently —Br. Inembodiments, X¹ is independently —I. In embodiments, X² is independently—F. In embodiments, X² is independently —Cl. In embodiments, X² isindependently —Br. In embodiments, X² is independently —I. Inembodiments, X⁶ is independently —F. In embodiments, X⁶ is independently—Cl. In embodiments, X⁶ is independently —Br. In embodiments, X⁶ isindependently —I.

In embodiments, R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹,—OCX¹ ₃, —OCH₂X¹, —OCHX¹ ₂, unsubstituted C₁-C₄ alkyl, or unsubstituted2 to 4 membered heteroalkyl; R² is independently halogen, —CX² ₃, —CHX²₂, —CH₂X², —OCX² ₃, —OCH₂X², —OCHX² ₂, unsubstituted C₁-C₄ alkyl, orunsubstituted 2 to 4 membered heteroalkyl; L³ is a bond, —N(R³)—,—C(O)—, —C(O)N(R³)—, —N(R³)C(O)—, —N(H)—, —C(O)N(H)—, —N(H)C(O)—,—C(O)O—, R³-substituted or unsubstituted C₁-C₆ alkylene, orR³-substituted or unsubstituted 2 to 6 membered heteroalkylene; R³ isindependently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂,—CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂,—NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃,—OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I,—OCH₂F, —N₃, —SF₅, R⁴-substituted or unsubstituted C₁-C₈ alkyl,R⁴-substituted or unsubstituted 2 to 8 membered heteroalkyl,R⁴-substituted or unsubstituted C₃-C₈ cycloalkyl, R⁴-substituted orunsubstituted 3 to 8 membered heterocycloalkyl, R⁴-substituted orunsubstituted C₆-C₁₀ aryl, or R⁴-substituted or unsubstituted 5 to 10membered heteroaryl; R⁴ is independently oxo, halogen, —CCl₃, —CBr₃,—CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R⁵-substituted or unsubstitutedC₁-C₈ alkyl, R⁵-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R⁵-substituted or unsubstituted C₃-C₅ cycloalkyl,R⁵-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R⁵-substituted or unsubstituted C₆-C₁₀ aryl, or R⁵-substituted orunsubstituted 5 to 10 membered heteroaryl; R⁵ is independently oxo,halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl,—CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂,—OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SFS,unsubstituted C₁-C₈ alkyl, unsubstituted 2 to 8 membered heteroalkyl,unsubstituted C₃-C₅ cycloalkyl, unsubstituted 3 to 8 memberedheterocycloalkyl, unsubstituted C₆-C₁₀ aryl, or unsubstituted 5 to 10membered heteroaryl; R⁶ is independently hydrogen, halogen, —CX⁶ ₃,—CHX⁶ ₂, —CH₂X⁶, —OCX⁶ ₃, —OCH₂X⁶, —OCHX⁶ ₂, —CN, —SR^(6D), —SOR^(6D),—SO₂R^(6D), —SO₃R^(6D)—SO₄R^(6D), —SONR^(6A)R^(6B), —SO₂NR^(6A)R^(6B),—NR^(6C)C(O)NR^(6A)R^(6B), —N(O), —N(O)₂, —NR^(6A)R^(6B), —C(O)R^(6C),—C(O)—OR^(6C), —C(O)NR^(6A)R^(6B), —OR^(6D), —NR^(6A)SO₂R^(6D),—NR^(6A)C(O)R^(6C), —NR^(6A)C(O)OR^(6C), —NR^(6A)OR^(6C),—NR^(6C)NR^(6A)R^(6B), —C(O)NR^(6C)NR^(6A)R^(6B), R⁷-substituted orunsubstituted C₁-C₈ alkyl, R⁷-substituted or unsubstituted 2 to 8membered heteroalkyl, R⁷-substituted or unsubstituted C₃-C₅ cycloalkyl,R⁷-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R⁷-substituted or unsubstituted C₆-C₁₀ aryl, or R⁷-substituted orunsubstituted 5 to 10 membered heteroaryl; R⁷ is independently oxo,halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl,—CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂,—OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅,R⁸-substituted or unsubstituted C₁-C₅ alkyl, R⁸-substituted orunsubstituted 2 to 8 membered heteroalkyl, R⁸-substituted orunsubstituted C₃-C₅ cycloalkyl, R⁸-substituted or unsubstituted 3 to 8membered heterocycloalkyl, R⁸-substituted or unsubstituted C₆-C₁₀ aryl,or R⁸-substituted or unsubstituted 5 to 10 membered heteroaryl; R⁸ isindependently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂,—CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂,—NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃,—OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I,—OCH₂F, —N₃, —SF₅, R⁹-substituted or unsubstituted C₁-C₈ alkyl,R⁹-substituted or unsubstituted 2 to 8 membered heteroalkyl,R⁹-substituted or unsubstituted C₃-C₅ cycloalkyl, R⁹-substituted orunsubstituted 3 to 8 membered heterocycloalkyl, R⁹-substituted orunsubstituted C₆-C₁₀ aryl, or R⁹-substituted or unsubstituted 5 to 10membered heteroaryl; R⁹ is independently oxo, halogen, —CCl₃, —CBr₃,—CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted C₁-C₈ alkyl,unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C₃-C₅cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl,unsubstituted C₆-C₁₀ aryl, or unsubstituted 5 to 10 membered heteroaryl;R^(6A) is independently hydrogen, oxo, halogen, —CCl₃, —CBr₃, —CF₃,—CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(7A)-substituted or unsubstitutedC₁-C₈ alkyl, R^(7A)-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R^(7A)-substituted or unsubstituted C₃-C₈ cycloalkyl,R^(7A)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R^(7A)-substituted or unsubstituted C₆-C₁₀ aryl, or R^(7A)-substitutedor unsubstituted 5 to 10 membered heteroaryl; R^(7A) is independentlyoxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂,—CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂,—OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅,R^(8A)-substituted or unsubstituted C₁-C₈ alkyl, R^(8A)-substituted orunsubstituted 2 to 8 membered heteroalkyl, R^(8A)-substituted orunsubstituted C₃-C₈ cycloalkyl, R^(8A)-substituted or unsubstituted 3 to8 membered heterocycloalkyl, R^(8A)-substituted or unsubstituted C₆-C₁₀aryl, or R^(8A)-substituted or unsubstituted 5 to 10 memberedheteroaryl; R^(8A) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃,—CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(9A)-substituted or unsubstitutedC₁-C₈ alkyl, R^(9A)-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R^(9A)-substituted or unsubstituted C₃-C₈ cycloalkyl,R^(9A)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R^(9A)-substituted or unsubstituted C₆-C₁₀ aryl, or R^(9A)-substitutedor unsubstituted 5 to 10 membered heteroaryl; R^(9A) is independentlyoxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂,—CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂,—OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SFS,unsubstituted C₁-C₈ alkyl, unsubstituted 2 to 8 membered heteroalkyl,unsubstituted C₃-C₈ cycloalkyl, unsubstituted 3 to 8 memberedheterocycloalkyl, unsubstituted C₆-C₁₀ aryl, or unsubstituted 5 to 10membered heteroaryl; R^(6B) is independently hydrogen, oxo, halogen,—CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br,—CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂,—OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅,R^(7B)-substituted or unsubstituted C₁-C₈ alkyl, R^(7B)-substituted orunsubstituted 2 to 8 membered heteroalkyl, R^(7B)-substituted orunsubstituted C₃-C₈ cycloalkyl, R^(7B)-substituted or unsubstituted 3 to8 membered heterocycloalkyl, R^(7B)-substituted or unsubstituted C₆-C₁₀aryl, or R^(7B)-substituted or unsubstituted 5 to 10 memberedheteroaryl; R^(7B) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃,—CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(8B)-substituted or unsubstitutedC₁-C₈ alkyl, R^(8B)-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R^(8B)-substituted or unsubstituted C₃-C₈ cycloalkyl,R^(8B)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R^(8B)-substituted or unsubstituted C₆-C₁₀ aryl, or R^(8B)-substitutedor unsubstituted 5 to 10 membered heteroaryl; R^(8B) is independentlyoxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂,—CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂,—OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅,R^(9B)-substituted or unsubstituted C₁-C₈ alkyl, R^(9B)-substituted orunsubstituted 2 to 8 membered heteroalkyl, R^(9B)-substituted orunsubstituted C₃-C₈ cycloalkyl, R^(9B)-substituted or unsubstituted 3 to8 membered heterocycloalkyl, R^(9B)-substituted or unsubstituted C₆-C₁₀aryl, or R^(9B)-substituted or unsubstituted 5 to 10 memberedheteroaryl; R^(9B) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃,—CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted C₁-C₈ alkyl,unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C₃-C₈cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl,unsubstituted C₆-C₁₀ aryl, or unsubstituted 5 to 10 membered heteroaryl;R^(6C) is independently hydrogen, oxo, halogen, —CCl₃, —CBr₃, —CF₃,—CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂CI,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(7C)-substituted or unsubstitutedC₁-C₈ alkyl, R^(7C)-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R^(7C)-substituted or unsubstituted C₃-C₈ cycloalkyl,R^(7C)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R^(7C)-substituted or unsubstituted C₆-C₁₀ aryl, or R^(7C)-substitutedor unsubstituted 5 to 10 membered heteroaryl; R^(7C) is independentlyoxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂,—CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂,—OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅,—NHR^(8C), R^(8C)-substituted or unsubstituted C₁-C₈ alkyl,R^(8C)-substituted or unsubstituted 2 to 8 membered heteroalkyl,R^(8C)-substituted or unsubstituted C₃-C₈ cycloalkyl, R^(8C)-substitutedor unsubstituted 3 to 8 membered heterocycloalkyl, R^(8C)-substituted orunsubstituted C₆-C₁₀ aryl, or R^(8C)-substituted or unsubstituted 5 to10 membered heteroaryl; R^(8C) is independently oxo, halogen, —CCl₃,—CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F,—CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH,—NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,—OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(9C)-substituted orunsubstituted C₁-C₈ alkyl, R^(9C)-substituted or unsubstituted 2 to 8membered heteroalkyl, R^(9C)-substituted or unsubstituted C₃-C₈cycloalkyl, R^(9C)-substituted or unsubstituted 3 to 8 memberedheterocycloalkyl, R^(9C)-substituted or unsubstituted C₆-C₁₀ aryl, orR^(9C)-substituted or unsubstituted 5 to 10 membered heteroaryl; R^(9C)is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂,—CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂,—NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃,—OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I,—OCH₂F, —N₃, —SF₅, unsubstituted C₁-C₈ alkyl, unsubstituted 2 to 8membered heteroalkyl, unsubstituted C₃-C₈ cycloalkyl, unsubstituted 3 to8 membered heterocycloalkyl, unsubstituted C₆-C₁₀ aryl, or unsubstituted5 to 10 membered heteroaryl; R^(6D) is independently hydrogen, oxo,halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl,—CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂,—OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂CI, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅,R^(7D)-substituted or unsubstituted C₁-C₈ alkyl, R^(7D)-substituted orunsubstituted 2 to 8 membered heteroalkyl, R^(7D)-substituted orunsubstituted C₃-C₈ cycloalkyl, R^(7D)-substituted or unsubstituted 3 to8 membered heterocycloalkyl, R^(7D)-substituted or unsubstituted C₆-C₁₀aryl, or R^(7D)-substituted or unsubstituted 5 to 10 memberedheteroaryl; R^(7D) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃,—CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(8D)-substituted or unsubstitutedC₁-C₈ alkyl, R^(8D)-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R^(8D)-substituted or unsubstituted C₃-C₈ cycloalkyl,R^(8D)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R^(8D)-substituted or unsubstituted C₆-C₁₀ aryl, or R^(8D)-substitutedor unsubstituted 5 to 10 membered heteroaryl; R^(8D) is independentlyoxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂,—CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂,—OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅,R^(9D)-substituted or unsubstituted C₁-C₈ alkyl, R^(9D)-substituted orunsubstituted 2 to 8 membered heteroalkyl, R^(9D)-substituted orunsubstituted C₃-C₈ cycloalkyl, R^(9D)-substituted or unsubstituted 3 to8 membered heterocycloalkyl, R^(9D)-substituted or unsubstituted C₆-C₁₀aryl, or R^(9D)-substituted or unsubstituted 5 to 10 memberedheteroaryl; R^(9D) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃,—CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SFS, unsubstituted C₁-C₈ alkyl,unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C₃-C₈cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl,unsubstituted C₆-C₁₀ aryl, or unsubstituted 5 to 10 membered heteroaryl;and X¹, X², and X⁶ are independently —F, —Cl, —Br, or —I.

In embodiments, R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹,—OCX¹ ₃, —OCH₂X¹, —OCHX¹ ₂, unsubstituted C₁-C₄ alkyl, or unsubstituted2 to 4 membered heteroalkyl; R² is independently halogen, —CX² ₃, —CHX²₂, —CH₂X², —OCX² ₃, —OCH₂X², —OCHX² ₂, unsubstituted C₁-C₄ alkyl, orunsubstituted 2 to 4 membered heteroalkyl; L³ is a bond, —N(R³)—,—C(O)—, —C(O)N(R³)—, —N(R³)C(O)—, —N(H)—, —C(O)N(H)—, —N(H)C(O)—,—C(O)O—, R³-substituted or unsubstituted C₁-C₆ alkylene, orR³-substituted or unsubstituted 2 to 6 membered heteroalkylene; R³ isindependently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂,—CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂,—NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃,—OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I,—OCH₂F, —N₃, —SF₅, R⁴-substituted or unsubstituted C₁-C₈ alkyl,R⁴-substituted or unsubstituted 2 to 8 membered heteroalkyl,R⁴-substituted or unsubstituted C₃-C₈ cycloalkyl, R⁴-substituted orunsubstituted 3 to 8 membered heterocycloalkyl, R⁴-substituted orunsubstituted C₆-C₁₀ aryl, or R⁴-substituted or unsubstituted 5 to 10membered heteroaryl; R⁴ is independently oxo, halogen, —CCl₃, —CBr₃,—CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R⁵-substituted or unsubstitutedC₁-C₈ alkyl, R⁵-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R⁵-substituted or unsubstituted C₃-C₈ cycloalkyl,R⁵-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R⁵-substituted or unsubstituted C₆-C₁₀ aryl, or R⁵-substituted orunsubstituted 5 to 10 membered heteroaryl; R⁵ is independently oxo,halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl,—CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂,—OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SFS,unsubstituted C₁-C₈ alkyl, unsubstituted 2 to 8 membered heteroalkyl,unsubstituted C₃-C₈ cycloalkyl, unsubstituted 3 to 8 memberedheterocycloalkyl, unsubstituted C₆-C₁₀ aryl, or unsubstituted 5 to 10membered heteroaryl; R⁶ is independently hydrogen, halogen, —CX⁶ ₃,—CHX⁶ ₂, —CH₂X⁶, —OCX⁶ ₃, —OCH₂X⁶, —OCHX⁶ ₂, —CN, —SR^(6D), —SOR^(6D),—SO₂R^(6D), —SO₃R^(6D), —SO₄R^(6D), —SONR^(6A)R^(6B), —SO₂NR^(6A)R^(6B),—NR^(6C)C(O)NR^(6A)R^(6B), —N(O), —N(O)₂, —NR^(6A)R^(6B), —C(O)R^(6C),—C(O)—OR^(6C), —C(O)NR^(6A)R^(6B), —OR^(6D), —NR^(6A)SO₂R^(6D),—NR^(6A)C(O)R^(6C), —NR^(6A)C(O)OR^(6C), —NR^(6A)OR^(6C),—NR^(6C)NR^(6A)R^(6B), —C(O)NR^(6C)NR^(6A)R^(6B), R⁷-substituted orunsubstituted C₁-C₈ alkyl, R⁷-substituted or unsubstituted 2 to 8membered heteroalkyl, R⁷-substituted or unsubstituted C₃-C₈ cycloalkyl,R⁷-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R⁷-substituted or unsubstituted C₆-C₁₀ aryl, or R⁷-substituted orunsubstituted 5 to 10 membered heteroaryl; R⁷ is independently oxo,halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl,—CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂,—OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅,R⁸-substituted or unsubstituted C₁-C₅ alkyl, R⁷-substituted orunsubstituted 2 to 8 membered heteroalkyl, R⁷-substituted orunsubstituted C₃-C₈ cycloalkyl, R⁸-substituted or unsubstituted 3 to 8membered heterocycloalkyl, R⁷-substituted or unsubstituted C₆-C₁₀ aryl,or R⁸-substituted or unsubstituted 5 to 10 membered heteroaryl; R⁷ isindependently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂,—CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂,—NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃,—OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I,—OCH₂F, —N₃, —SF₅, unsubstituted C₁-C₈ alkyl, unsubstituted 2 to 8membered heteroalkyl, unsubstituted C₃-C₈ cycloalkyl, unsubstituted 3 to8 membered heterocycloalkyl, unsubstituted C₆-C₁₀ aryl, or unsubstituted5 to 10 membered heteroaryl; R^(6A) is independently hydrogen, oxo,halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl,—CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂,—OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅,R^(7A)-substituted or unsubstituted C₁-C₈ alkyl, R^(7A)-substituted orunsubstituted 2 to 8 membered heteroalkyl, R^(7A)-substituted orunsubstituted C₃-C₈ cycloalkyl, R^(7A)-substituted or unsubstituted 3 to8 membered heterocycloalkyl, R^(7A)-substituted or unsubstituted C₆-C₁₀aryl, or R^(7A)-substituted or unsubstituted 5 to 10 memberedheteroaryl; R^(7A) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃,—CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂CI,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(8A)-substituted or unsubstitutedC₁-C₈ alkyl, R^(8A)-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R^(8A)-substituted or unsubstituted C₃-C₈ cycloalkyl,R^(8A)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R^(8A)-substituted or unsubstituted C₆-C₁₀ aryl, or R^(8A)-substitutedor unsubstituted 5 to 10 membered heteroaryl; R^(8A) is independentlyoxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂,—CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂,—OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅,unsubstituted C₁-C₈ alkyl, unsubstituted 2 to 8 membered heteroalkyl,unsubstituted C₃-C₈ cycloalkyl, unsubstituted 3 to 8 memberedheterocycloalkyl, unsubstituted C₆-C₁₀ aryl, or unsubstituted 5 to 10membered heteroaryl; R^(6B) is independently hydrogen, oxo, halogen,—CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br,—CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂,—OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅,R^(7B)-substituted or unsubstituted C₁-C₈ alkyl, R^(7B)-substituted orunsubstituted 2 to 8 membered heteroalkyl, R^(7B)-substituted orunsubstituted C₃-C₈ cycloalkyl, R^(7B)-substituted or unsubstituted 3 to8 membered heterocycloalkyl, R^(7B)-substituted or unsubstituted C₆-C₁₀aryl, or R^(7B)-substituted or unsubstituted 5 to 10 memberedheteroaryl; R^(7B) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃,—CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(8B)-substituted or unsubstitutedC₁-C₈ alkyl, R^(8B)-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R^(8B)-substituted or unsubstituted C₃-C₈ cycloalkyl,R^(8B)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R^(8B)-substituted or unsubstituted C₆-C₁₀ aryl, or R^(8B)-substitutedor unsubstituted 5 to 10 membered heteroaryl; R^(8B) is independentlyoxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂,—CH₂CI, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂,—OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂CI, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅,unsubstituted C₁-C₅ alkyl, unsubstituted 2 to 8 membered heteroalkyl,unsubstituted C₃-C₈ cycloalkyl, unsubstituted 3 to 8 memberedheterocycloalkyl, unsubstituted C₆-C₁₀ aryl, or unsubstituted 5 to 10membered heteroaryl; R^(6C) is independently hydrogen, oxo, halogen,—CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br,—CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂,—OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅,R^(7C)-substituted or unsubstituted C₁-C₅ alkyl, R^(7C)-substituted orunsubstituted 2 to 8 membered heteroalkyl, R^(7C)-substituted orunsubstituted C₃-C₈ cycloalkyl, R^(7C)-substituted or unsubstituted 3 to8 membered heterocycloalkyl, R^(7C)-substituted or unsubstituted C₆-C₁₀aryl, or R^(7C)-substituted or unsubstituted 5 to 10 memberedheteroaryl; R^(7C) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃,—CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SFS, —NHR^(8C), R^(8C)-substituted orunsubstituted C₁-C₅ alkyl, R^(8C)-substituted or unsubstituted 2 to 8membered heteroalkyl, R^(8C)-substituted or unsubstituted C₃-C₈cycloalkyl, R^(8C)-substituted or unsubstituted 3 to 8 memberedheterocycloalkyl, R^(8C)-substituted or unsubstituted C₆-C₁₀ aryl, orR^(8C)-substituted or unsubstituted 5 to 10 membered heteroaryl; R^(8C)is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂,—CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂,—NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃,—OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I,—OCH₂F, —N₃, —SF₅, R^(9C)-substituted or unsubstituted C₁-C₈ alkyl,R^(9C)-substituted or unsubstituted 2 to 8 membered heteroalkyl,R^(9C)-substituted or unsubstituted C₃-C₈ cycloalkyl, R^(9C)-substitutedor unsubstituted 3 to 8 membered heterocycloalkyl, R^(9C)-substituted orunsubstituted C₆-C₁₀ aryl, or R^(9C)-substituted or unsubstituted 5 to10 membered heteroaryl; R^(9C) is independently oxo, halogen, —CCl₃,—CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F,—CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH,—NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,—OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted C₁-C₈ alkyl,unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C₃-C₈cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl,unsubstituted C₆-C₁₀ aryl, or unsubstituted 5 to 10 membered heteroaryl;R^(6D) is independently hydrogen, oxo, halogen, —CCl₃, —CBr₃, —CF₃,—CI₃, CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(7D)-substituted or unsubstitutedC₁-C₈ alkyl, R^(7D)-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R^(7D)-substituted or unsubstituted C₃-C₈ cycloalkyl,R^(7D)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R^(7D)-substituted or unsubstituted C₆-C₁₀ aryl, or R^(7D)-substitutedor unsubstituted 5 to 10 membered heteroaryl; R^(7D) is independentlyoxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂,—CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂,—OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅,R^(8D)-substituted or unsubstituted C₁-C₈ alkyl, R^(8D)-substituted orunsubstituted 2 to 8 membered heteroalkyl, R^(8D)-substituted orunsubstituted C₃-C₈ cycloalkyl, R^(8D)-substituted or unsubstituted 3 to8 membered heterocycloalkyl, R^(8D)-substituted or unsubstituted C₆-C₁₀aryl, or R^(8D)-substituted or unsubstituted 5 to 10 memberedheteroaryl; R^(8D) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃,—CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted C₁-C₈ alkyl,unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C₃-C₈cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl,unsubstituted C₆-C₁₀ aryl, or unsubstituted 5 to 10 membered heteroaryl;and X¹, X², and X⁶ are independently —F, —Cl, —Br, or —I.

In embodiments, -L³-R⁶ is independently O

In embodiments, -L³-R⁶ is

In embodiments, -L³-R⁶ is independently

In embodiments, -L³-R⁶ is not

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In embodiments, the compound is:

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In embodiments, the compound is not

In embodiments, the compound is not

In embodiments, the compound is not

In embodiments, the compound is not

In embodiments, the compound is not

In embodiments, the compound is not

In embodiments, the compound is not

In embodiments, the compound is not

In embodiments, the compound is not

In embodiments, the compound is not

In embodiments, the compound is not

In embodiments, the compound is not

In embodiments, the compound is not

In embodiments, the compound is not

In embodiments, the compound is not

In embodiments, the compound is not

In embodiments, the compound is not

In embodiments, the compound is not

In embodiments, the compound is not

In embodiments, the compound is not

In embodiments, the compound is not

In embodiments, the compound is not

In embodiments, the compound is not

In embodiments, the compound is not

In embodiments, the compound is not

In embodiments, the compound is not

In embodiments, the compound is not

In embodiments, the compound is not

In embodiments, L³ is a R³-substituted or unsubstituted C₁-C₆ alkylene,or R³-substituted or unsubstituted 2 to 6 membered heteroalkylene,wherein R³ is oxo, —COOH, unsubstituted C₁-C₄ alkyl, or unsubstitutedphenyl.

In embodiments, L³ is independently a R³-substituted or unsubstitutedC₁-C₆ alkylene, or R³-substituted or unsubstituted 2 to 6 memberedheteroalkylene, wherein R³ is oxo, —COOH, unsubstituted C₁-C₄ alkyl, orunsubstituted phenyl.

In embodiments, L³ is a R³-substituted or unsubstituted C₁-C₆ alkylene,or R³-substituted or unsubstituted 2 to 6 membered heteroalkylene, andR⁶ is an R⁷-substituted phenyl.

In embodiments, L³ is independently a R³-substituted or unsubstitutedC₁-C₆ alkylene, or R³-substituted or unsubstituted 2 to 6 memberedheteroalkylene, and R⁶ is an R⁷-substituted phenyl.

In embodiments, L³ is a R³-substituted or unsubstituted C₁-C₆ alkylene,or R³-substituted or unsubstituted 2 to 6 membered heteroalkylene, andR⁶ is an R⁷-substituted heterocycloalkyl. In embodiments, L³ is aR³-substituted C₁-C₆ alkylene, or R³-substituted 2 to 6 memberedheteroalkylene, wherein R³ is oxo, —COOH, unsubstituted C₁-C₄ alkyl, orunsubstituted phenyl; and R⁶ is an R⁷-substituted heterocycloalkyl. Inembodiments, L³ is a R³-substituted or unsubstituted C₁-C₆ alkylene, orR³-substituted or unsubstituted 2 to 6 membered heteroalkylene, and R⁶is an unsubstituted heterocycloalkyl.

In embodiments, L³ is independently a R³-substituted or unsubstitutedC₁-C₆ alkylene, or R³-substituted or unsubstituted 2 to 6 memberedheteroalkylene, and R⁶ is independently an R⁷-substitutedheterocycloalkyl. In embodiments, L³ is independently a R³-substitutedC₁-C₆ alkylene, or R³-substituted 2 to 6 membered heteroalkylene,wherein R³ is independently oxo, —COOH, unsubstituted C₁-C₄ alkyl, orunsubstituted phenyl; and R⁶ is independently an R⁷-substitutedheterocycloalkyl. In embodiments, L³ is independently a R³-substitutedor unsubstituted C₁-C₆ alkylene, or R³-substituted or unsubstituted 2 to6 membered heteroalkylene, and R⁶ is independently an unsubstitutedheterocycloalkyl.

In embodiments, the compound has the formula

wherein R³ and R⁷ are as described herein. In embodiments, R⁷ isindependently an R⁸-substituted phenyl. In embodiments, R⁸ isindependently unsubstituted methoxy.

In embodiments, the compound has the formula

wherein R³ and R⁷ are as described herein. In embodiments, R⁷ isindependently an R⁸-substituted phenyl. In embodiments, R⁸ isindependently unsubstituted methoxy.

In embodiments, the compound is

wherein R⁷ is as described herein. In embodiments, R⁷ is anR⁸-substituted C₁-C₄ alkyl. In embodiments, R⁸ is an unsubstitutedphenyl.

In embodiments, the compound has the formula

wherein R⁷ is as described herein. In embodiments, R⁷ is independentlyan R⁸-substituted C₁-C₄ alkyl. In embodiments, R⁸ is independently anunsubstituted phenyl.

In embodiments, the compound has the formula

R^(8.1) and R^(8.2) may each independently be any value of R⁸ asdescribed herein, including in embodiments, or hydrogen. In embodiments,R^(8.1) and R^(8.2) are each independently unsubstituted methoxy.

In embodiments, the compound has the formula

wherein R³ and R⁷ are as described herein. In embodiments, R⁷ isindependently an R⁸-substituted 2 to 4 membered heteroalkyl. Inembodiments, R⁷ is independently —NHC(O)CH₃.

In embodiments, the compound has the formula

wherein R³ and R⁶ are as described herein. In embodiments, R³ isindependently an unsubstituted C1-C4 alkyl. In embodiments, R³ isindependently an unsubstituted isopropyl. In embodiments, R³ isindependently an unsubstituted isobutyl. In embodiments, R⁶ isindependently hydrogen.

In embodiments, the compound has the formula

wherein R³ and R⁷ are as described herein. In embodiments, R⁷ isindependently an R⁸-substituted 3 to 7 membered heteroalkyl. Inembodiments, R⁸ is independently oxo.

In embodiments, the compound has the formula

wherein R³ is as described herein. R^(7.1), R^(7.2), R^(7.3), R^(7.4),and R^(7.5) may each independently be any value of R⁷ as describedherein, including in embodiments, or hydrogen. In embodiments, R^(7.1)is independently unsubstituted methoxy. In embodiments, R⁷ isindependently halogen. In embodiments, R^(7.1) is independently —Cl. Inembodiments, R^(7.3) is independently a halogen. In embodiments, R^(7.3)is independently —Cl. In embodiments, R^(7.4) is independentlyunsubstituted methoxy. In embodiments, R^(7.1) and R^(7.5) are eachindependently unsubstituted C₁-C₄ alkyl. In embodiments, R^(7.1) andR^(7.5) are each independently unsubstituted ethyl.

In embodiments, the compound has the formula

wherein R³ and R⁷ are as described herein. In embodiments, R isindependently halogen. In embodiments, R⁷ is independently —Cl.

In embodiments, the compound has the formula

wherein R³ is as described herein. R^(7.1), R^(7.2), R^(7.3), R^(7.4),and R^(7.5) may each independently be any value of R⁷ as describedherein, including in embodiments, or hydrogen. In embodiments, R^(7.1)is independently unsubstituted methoxy. In embodiments, R^(7.3) isindependently an oxo-substituted C₁-C₄ alkyl. In embodiments, R^(7.3) isindependently —C(O)CH₃.

In embodiments, the compound has the formula

wherein R³ and R⁷ are as described herein. In embodiments, R³ isindependently an unsubstituted C₁-C₄ alkyl. In embodiments, R⁷ isindependently halogen. In embodiments, R⁷ is independently —Br.

In embodiments, the compound has the formula

wherein R³ and R⁷ are as described herein. In embodiments, R⁷ isindependently halogen. In embodiments, R⁷ is independently —Br.

In embodiments, the compound has the formula

wherein R³ and R⁶ is as described herein. In embodiments, R⁶ isindependently an unsubstituted phenyl. In embodiments, R³ isindependently an unsubstituted C₁-C₆ alkylene.

In embodiments, the compound has the formula

wherein R³ and R⁷ are as described herein. In embodiments, R³ isindependently an unsubstituted phenyl. In embodiments, R⁷ isindependently an unsubstituted C₁-C₄ alkyl. In embodiments, R⁷ isindependently unsubstituted methyl.

In embodiments, the compound has the formula

wherein R³ is as described herein. R^(7.1), R^(7.2), R^(7.3), R^(7.4),and R^(7.5) may each independently be any value of R⁷ as describedherein, including in embodiments, or hydrogen. In embodiments, R^(7.3)is independently unsubstituted phenyl. In embodiments, R^(7.1) andR^(7.3) are each independently halogen. In embodiments, R^(7.1) andR^(7.3) are each independently —Cl.

In embodiments, the compound has the formula

wherein R³ and R⁶ are as described herein. In embodiments, R³ isindependently —COOH. In embodiments, R⁶ is independently

In embodiments, R⁶ is independently

In embodiments, the compound has the formula

wherein R⁹ is as described herein. In embodiments, R⁹ is independentlyan unsubstituted C₁-C₄ alkyl. In embodiments, R⁹ is independently anunsubstituted isopropyl.

In embodiments, the compound has the formula

wherein R³ and R^(6D) are as described herein. In embodiments, R³ isindependently —COOH. In embodiments, R^(6D) is independentlyunsubstituted C₁-C₄ alkyl. In embodiments, R^(6D) is independentlyunsubstituted methyl.

In embodiments, the compound has the formula

wherein R⁷ is as described herein. In embodiments, R⁷ is independentlyunsubstituted C₁-C₄ alkyl. In embodiments, R⁷ is independentlyunsubstituted isopropyl.

In embodiments, the compound has the formula

wherein R³ and R⁷ are as described herein. In embodiments, R⁷ isindependently unsubstituted C₁-C₄ alkyl. In embodiments, R⁷ isindependently unsubstituted methyl.

In embodiments, the compound has the formula

wherein R⁷ is as described herein. In embodiments, R⁷ is independentlyan unsubstituted pyridyl. In embodiments, R⁷ is independently anunsubstituted 3-pyridyl.

In embodiments, the compound has the formula

wherein R³ and R⁶ are as described herein. In embodiments, R³ isindependently —COOH. In embodiments, R⁶ is independently unsubstitutedmorpholinyl.

In embodiments, the compound has the formula

wherein R³ and R^(7B) are as described herein. In embodiments, R^(7B) isindependently

In embodiments, R^(7B) is independently

In embodiments, the compound has the formula

wherein R³ and R^(7B) are as described herein. In embodiments, R^(7B) isindependently an unsubstituted pyridyl. In embodiments, R^(7B) isindependently an unsubstituted 3-pyridyl.

In embodiments, the compound has the formula

wherein R^(7C) is as described herein. In embodiments, R^(7C) isindependently an R^(8C)-substituted 4 to 8 membered heteroalkyl. Inembodiments, R^(8C) is independently oxo.

In embodiments, the compound has the formula

wherein R³ and R⁶ are as described herein. In embodiments, R³ isindependently —COOH. In embodiments, R⁶ is independently hydrogen.

In embodiments, the compound has the formula

wherein R³ is as described herein. In embodiments, R³ is independently—COOH.

In embodiments, the compound is

wherein R³ and R⁷ are as described herein. In embodiments, R⁷ isindependently an R⁸-substituted 3 to 7 membered heteroalkyl. Inembodiments, R⁸ is independently oxo.

In embodiments, the compound has the formula

wherein R³ is as described herein. R^(7.1), R^(7.2), R^(7.3), R^(7.4),and R^(7.5) may each independently be any value of R⁷ as describedherein, including in embodiments, or hydrogen. In embodiments, R^(7.1)is independently unsubstituted methoxy. In embodiments, R^(7.1) isindependently halogen. In embodiments, R^(7.1) is independently —Cl. Inembodiments, R^(7.3) is independently a halogen. In embodiments, R^(7.3)is independently —Cl. In embodiments, R^(7.4) is independentlyunsubstituted methoxy. In embodiments, R^(7.1) and R^(7.5) are eachindependently unsubstituted C₁-C₄ alkyl. In embodiments, R^(7.1) andR^(7.5) are each independently unsubstituted ethyl.

In embodiments, the compound is

wherein R³ and R⁷ are as described herein. In embodiments, R⁷ isindependently halogen. In embodiments, R⁷ is independently —Cl.

In embodiments, the compound has the formula

wherein R³ is as described herein. R^(7.1), R^(7.2), R^(7.3), R^(7.4),and R^(7.5) may each independently be any value of R⁷ as describedherein, including in embodiments, or hydrogen. In embodiments, R^(7.1)is independently unsubstituted methoxy. In embodiments, R^(7.3) isindependently an oxo-substituted C₁-C₄ alkyl. In embodiments, R^(7.3) isindependently —C(O)CH₃.

In embodiments, the compound has the formula

wherein R³ and R⁷ are as described herein. In embodiments, R³ isindependently an unsubstituted C₁-C₄ alkyl. In embodiments, R⁷ isindependently halogen. In embodiments, R⁷ is independently —Br.

In embodiments, the compound is

wherein R³ and R⁷ are as described herein. In embodiments, R⁷ ishalogen. In embodiments, R⁷ is —Br.

In embodiments, the compound has the formula

wherein R³ and R⁷ are as described herein. In embodiments, R⁷ isindependently halogen. In embodiments, R⁷ is independently —Br.

In embodiments, the compound is

wherein R³ and R⁶ is as described herein. In embodiments, R⁶ is anunsubstituted phenyl. In embodiments, R³ is an unsubstituted C₁-C₆alkylene.

In embodiments, the compound has the formula

wherein R³ and R⁶ are as described herein. In embodiments, R⁶ isindependently an unsubstituted phenyl. In embodiments, R³ isindependently an unsubstituted C₁-C₆ alkylene.

In embodiments, the compound has the formula

wherein R³ and R⁶ are as described herein. In embodiments, R⁶ isindependently an unsubstituted phenyl. In embodiments, R³ isindependently an unsubstituted C₁-C₆ alkylene.

In embodiments, the compound is

wherein R³ and R⁷ are as described herein.

In embodiments, the compound has the formula

wherein R³ and R⁷ are as described herein. In embodiments, R³ isindependently an unsubstituted phenyl. In embodiments, R⁸ isindependently an unsubstituted C₁-C₄ alkyl. In embodiments, R⁷ isindependently unsubstituted methyl.

In embodiments, the compound has the formula

wherein R³ is as described herein. R^(7.1), R^(7.2), R^(7.3), R^(7.4),and R^(7.5) may each independently be any value of R⁷ as describedherein, including in embodiments, or hydrogen. In embodiments, R^(7.3)is independently unsubstituted phenyl. In embodiments, R^(7.1) andR^(7.3) are each independently halogen. In embodiments, R^(7.1) andR^(7.3) are each independently —Cl.

In embodiments, the compound has the formula

wherein R³ and R⁶ are as described herein. In embodiments, R³ isindependently —COOH. In embodiments, R⁶ is independently

In embodiments, the compound has the formula

wherein R⁹ is as described herein. In embodiments, R⁹ is independentlyan unsubstituted C₁-C₄ alkyl. In embodiments, R⁹ is independently anunsubstituted isopropyl.

In embodiments, the compound has the formula

wherein R³ and R^(6D) are as described herein. In embodiments, R₃ isindependently —COOH. In embodiments, R^(6D) is independentlyunsubstituted C₁-C₄ alkyl. In embodiments, R^(6D) is independentlyunsubstituted methyl.

In embodiments, the compound has the formula

wherein R⁷ is as described herein. In embodiments, R⁷ is independentlyunsubstituted C₁-C₄ alkyl. In embodiments, R⁷ is independentlyunsubstituted isopropyl.

In embodiments, the compound has the formula

wherein R³ and R⁷ are as described herein. In embodiments, R⁷ isindependently unsubstituted C₁-C₄ alkyl. In embodiments, R⁷ isindependently unsubstituted methyl.

In embodiments, the compound has the formula

wherein R⁷ is as described herein. In embodiments, R⁷ is independentlyan unsubstituted pyridyl. In embodiments, R⁷ is independently anunsubstituted 3-pyridyl.

In embodiments, the compound has the formula

wherein R³ and R⁶ are as described herein. In embodiments, R³ isindependently —COOH. In embodiments, R⁶ is independently unsubstitutedmorpholinyl.

In embodiments, the compound has the formula

wherein R³ and R^(7B) are as described herein. In embodiments, R^(7B) isindependently

In embodiments, the compound has the formula

wherein R³ and R^(7B) are as described herein. In embodiments, R^(7B) isindependently an unsubstituted pyridyl. In embodiments, R^(7B) isindependently an unsubstituted 3-pyridyl.

In embodiments, the compound has the formula

wherein R^(7C) is as described herein. In embodiments, R^(7C) isindependently an R^(8C)-substituted 4 to 8 membered heteroalkyl. Inembodiments, R^(8C) is independently oxo.

In embodiments, the compound has the formula

wherein R³ and R⁶ are as described herein. In embodiments, R³ isindependently —COOH. In embodiments, R⁶ is independently hydrogen.

In embodiments, the compound has the formula

wherein R³ is as described herein. In embodiments, R³ is independently—COOH.

In embodiments, the compound has the formula

wherein R³ and R⁶ are as described herein. In embodiments, R³ isindependently an unsubstituted C₁-C₄ alkyl. In embodiments, R⁶ isindependently hydrogen.

In embodiments, the compound has the formula

wherein R⁶ is as described herein. In embodiments, R⁶ is independentlyhydrogen.

In embodiments, the compound has the formula

wherein R³ and R⁶ are as described herein. In embodiments, R³ isindependently —COOH. In embodiments, R⁶ is independently hydrogen.

In embodiments, the compound has the formula

wherein R³ is as described herein. In embodiments, R³ is independently—COOH. In embodiments, R³ is independently unsubstituted C₁-C₄ alkyl. Inembodiments, R³ is independently unsubstituted isobutyl.

In embodiments, the compound has the formula

wherein is as described herein. In embodiments, R⁷ is independentlyhalogen. In embodiments, R⁷ is independently —Cl.

In embodiments, the compound has the formula

wherein R³ and R⁷ are as described herein. In embodiments, R³ isindependently unsubstituted C₁-C₄ alkyl. In embodiments, R³ isindependently unsubstituted isobutyl. In embodiments, R³ isindependently —COOH. In embodiments, R⁷ is independently halogen. Inembodiments, R⁷ is independently —Cl.

In embodiments, the compound has the formula

wherein R³ is as described herein. In embodiments, R³ is independently—COOH.

In embodiments, the compound does not have the formula

wherein R³ and R⁷ are as described herein.

In embodiments, the compound does not have the formula

wherein R⁷ is as described herein.

In embodiments, the compound does not have the formula

R^(8.1) and R^(8.2) may each independently be any value of R⁸ asdescribed herein, including in embodiments, or hydrogen.

In embodiments, the compound does not have the formula

wherein R³ and R⁶ are as described herein.

In embodiments, the compound does not have the formula

wherein R³ and R⁶ are as described herein.

In embodiments, the compound does not have the formula

wherein R³ and R⁷ are as described herein.

In embodiments, the compound does not have the formula

wherein R³ is as described herein. R^(7.1), R^(7.2), R^(7.3), R^(7.4),and R^(7.5) may each independently be any value of R⁷ as describedherein, including in embodiments, or hydrogen.

In embodiments, the compound does not have the formula

wherein R³ is as described herein. R^(7.1), R^(7.2), R^(7.3), R^(7.4),and R^(7.5) may each independently be any value of R⁷ as describedherein, including in embodiments, or hydrogen.

In embodiments, the compound does not have the formula

wherein R³ and R⁷ are as described herein.

In embodiments, the compound does not have the formula

wherein R³ and R⁶ are as described herein.

In embodiments, the compound does not have the formula

wherein R³ and R⁶ are as described herein.

In embodiments, the compound does not have the formula

wherein R³ and R⁷ are as described herein.

In embodiments, the compound does not have the formula

wherein R³ is as described herein. R^(7.1), R^(7.2), R^(7.3), R^(7.4),and R^(7.5) may each independently be any value of R⁷ as describedherein, including in embodiments, or hydrogen.

In embodiments, the compound does not have the formula

wherein R³ and R⁶ are as described herein.

In embodiments, the compound does not have the formula

wherein R⁹ is as described herein.

In embodiments, the compound does not have the formula

wherein R³ and R^(6D) are as described herein.

In embodiments, the compound does not have the formula

wherein R⁷ is as described herein.

In embodiments, the compound does not have the formula

wherein R³ and R⁷ are as described herein.

In embodiments, the compound does not have the formula

wherein R⁷ is as described herein.

In embodiments, the compound does not have the formula

wherein R³ and R⁶ are as described herein.

In embodiments, the compound does not have the formula

wherein R³ and R^(7B) are as described herein.

In embodiments, the compound does not have the formula

wherein R³ and R^(7B) are as described herein.

In embodiments, the compound does not have the formula

wherein R^(7C) is as described herein.

In embodiments, the compound does not have the formula

wherein R³ and R⁶ are as described herein.

In embodiments, the compound does not have the formula

wherein R³ and R⁶ are as described herein.

In embodiments, the compound does not have the formula

wherein R³ and R⁷ are as described herein. In embodiments, the compounddoes not have the formula

wherein R³ is as described herein.

In embodiments, the compound is a compound described herein (e.g., in anaspect, embodiment, example, table, figure, or claim).

III. Pharmaceutical Compositions

In an aspect is provided a pharmaceutical composition including acompound described herein, or pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable excipient.

In embodiments of the pharmaceutical compositions, the compound, orpharmaceutically acceptable salt thereof, is included in atherapeutically effective amount.

In embodiments of the pharmaceutical compositions, the pharmaceuticalcomposition includes a second agent (e.g. therapeutic agent). Inembodiments of the pharmaceutical compositions, the pharmaceuticalcomposition includes a second agent (e.g. therapeutic agent) in atherapeutically effective amount. In embodiments of the pharmaceuticalcompositions, the second agent is an agent for treating inflammation. Inembodiments of the pharmaceutical compositions, the second agent is anagent for treating diabetes. In embodiments, the second agent isinsulin, metformin, an angiotensin converting enzyme inhibitor, or acalcium channel blocker. In embodiments, the second agent is acarbose,miglitol, bromocriptine, aloglipton, linagliptin, saxagliptin,sitagliptin, albiglutide, dulaglutide, exenatide, liraglutide,semaglutide, nateglinide, repaglinide, dapagliflozin, canagliflozin,empagliflozin, ertugliflozin, glimepiride, gliclazide, glipizide,glyburide, chlorpropamide, tolazamide, tolbutamide, rosiglitazone, orpioglitazone.

IV. Methods of Use

In an aspect is provided a method of treating a TXNIP-TRXcomplex-associated disease, the method including administering to asubject in need thereof an effective amount of a TXNIP-TRX complexinhibitor. In an aspect is provided a method of treating a TXNIP-TRXcomplex-associated disease, the method including administering to asubject in need thereof an effective amount of a TXNIP-TRX complexinhibitor, wherein the TXNIP-TRX complex inhibitor is a compound asdescribed herein, including embodiments. In embodiments, the TXNIP-TRXcomplex inhibitor has the formula:

W¹, W², L³, and R⁶ are as described herein, including in embodiments.

W¹ is —CR¹═, —N═, or —CH═. W² is —CR²═, —N═, or —CH═. R¹ isindependently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —OCX¹ ₃, —OCH₂X¹, —OCHX¹₂, substituted or unsubstituted alkyl, or substituted or unsubstitutedheteroalkyl. R² is independently halogen, —CX² ₃, —CHX² ₂, —CH₂X², —OCX²₃, —OCH₂X², —OCHX² ₂, substituted or unsubstituted alkyl, or substitutedor unsubstituted heteroalkyl. L³ is a bond, —N(R³)—, —C(O)—,—C(O)N(R³)—, —N(R³)C(O)—, —N(H)—, —C(O)N(H)—, —N(H)C(O)—, —C(O)O—,substituted or unsubstituted alkylene, or substituted or unsubstitutedheteroalkylene. R³ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃,—CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl. R⁶ isindependently hydrogen, halogen, —CX⁶ ₃, —CHX⁶ ₂, —CH₂X⁶, —OCX⁶ ₃,—OCH₂X⁶, —OCHX⁶ ₂, —CN, —SR^(6D), —SOR^(6D), —SO₂R^(6D)—SO₃R^(6D),—SO₄R^(6D), —SONR^(6A)R^(6B), —SO₂NR^(6A)R^(6B),—NR^(6C)C(O)NR^(6A)R^(6B), —N(O), —N(O)₂, —NR^(6A)R^(6B), —C(O)R^(6C),—C(O)—OR^(6C), —C(O)NR^(6A)R^(6B), —OR^(6D), —NR^(6A)SO₂R^(6D),—NR^(6A)C(O)R^(6C), —NR^(6A)C(O)OR^(6C), —NR^(6A)OR^(6C),—NR^(6C)NR^(6A)R^(6B), —C(O)NR^(6C)NR^(6A)R^(6B), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl. R^(6A)R^(6B), R^(6C), and R^(6D) are eachindependently hydrogen, oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SFS, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl; and Xi,X², and X⁶ are independently —F, —Cl, —Br, or —I.

In embodiments, the TXNIP-TRX complex-associated disease is a metabolicdisorder, cardiovascular disease, or inflammatory disease. Inembodiments, the TXNIP-TRX complex-associated disease is a metabolicdisorder. In embodiments, the TXNIP-TRX complex-associated disease iscardiovascular disease. In embodiments, the TXNIP-TRX complex-associateddisease is inflammation.

In embodiments, the TXNIP-TRX complex-associated disease is a kidneydisease or an eye disease. In embodiments, the TXNIP-TRXcomplex-associated disease is a kidney disease. In embodiments, theTXNIP-TRX complex-associated disease is an eye disease.

In embodiments, the compound binds (e.g., forms a covalent bond) toTXNIP.

In an aspect is provided a method of treating a metabolic disorder,cardiovascular disease, or inflammatory disease, the method includingadministering to a subject in need thereof an effective amount of acompound, or pharmaceutically acceptable salt thereof, as describedherein, including embodiments. In embodiments, the compound has theformula:

W¹, W², L³, and R⁶ are as described herein, including in embodiments.

W¹ is —CR¹═, —N═, or —CH═. W² is —CR²═, —N═, or —CH═. R¹ isindependently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —OCX¹ ₃, —OCH₂X¹, —OCHX¹₂, substituted or unsubstituted alkyl, or substituted or unsubstitutedheteroalkyl. R² is independently halogen, —CX² ₃, —CHX² ₂, —CH₂X², —OCX²₃, —OCH₂X², —OCHX² ₂, substituted or unsubstituted alkyl, or substitutedor unsubstituted heteroalkyl. L³ is a bond, —N(R³)—, —C(O)—,—C(O)N(R³)—, —N(R³)C(O)—, —N(H)—, —C(O)N(H)—, —N(H)C(O)—, —C(O)O—,substituted or unsubstituted alkylene, or substituted or unsubstitutedheteroalkylene. R³ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃,—CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl. R⁶ isindependently hydrogen, halogen, —CX⁶ ₃, —CHX⁶ ₂, —CH₂X⁶, —OCX⁶ ₃,—OCH₂X⁶, —OCHX⁶ ₂, —CN, —SR^(6D), —SOR^(6D), —SO₂R^(6D)—SO₃R^(6D),—SO₄R^(6D), —SONR^(6A)R^(6B), —SO₂NR^(6A)R^(6B),—NR^(6C)C(O)NR^(6A)R^(6B), —N(O), —N(O)₂, —NR^(6A)R^(6B), —C(O)R^(6C),—C(O)—OR^(6C), —C(O)NR^(6A)R^(6B), —OR^(6D), —NR^(6A)SO₂R^(6D),—NR^(6A)C(O)R^(6C), —NR^(6A)C(O)OR^(6C), —NR^(6A)OR^(6C),—NR^(6C)NR^(6A)R^(6B), —C(O)NR^(6C)NR^(6A)R^(6B), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl. R^(6A)R^(6B), R^(6C), and R^(6D) are eachindependently hydrogen, oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl; and X¹,X², and X⁶ are independently —F, —Cl, —Br, or —I.

In embodiments, the method includes reducing side effects (e.g., lowerincidences of side effects) relative to alternative forms of treatment(e.g., administering verapamil). In embodiments, the side effectsinclude constipation, dizziness, headache, increased liver enzymes,indigestion, low blood pressure (hypotension), nausea, rash, shortnessof breath, sleep disturbance, swelling (edema), or swollen gums. Inembodiments, the side effect is constipation, dizziness, headache,increased liver enzymes, indigestion, low blood pressure (hypotension),nausea, rash, shortness of breath, sleep disturbance, swelling (edema),or swollen gums.

In embodiments, the compound is capable of inhibiting TXNIP proteinactivity or function, the method including contacting the TXNIP proteinwith the compound. In embodiments, the compound is capable of inhibitingTXNIP protein binding to TRX, the method including contacting the TXNIPprotein with the compound. In embodiments, the compound inhibits TXNIPprotein activity or function, the method including contacting the TXNIPprotein with the compound. In embodiments, the compound inhibits TXNIPprotein binding to TRX, the method including contacting the TXNIPprotein with the compound.

In embodiments, the metabolic disorder is diabetes. In embodiments, themetabolic disorder is type 1 diabetes (T1D). In embodiments, themetabolic disorder is type 2 diabetes (T2D). In embodiments, thediabetes is associated with islet beta cell dysfunction. In embodiments,the cardiovascular disease is atherosclerosis.

In embodiments, the disease (e.g., metabolic disorder) is diabetes(e.g., type 1 diabetes or type 2 diabetes), insulin resistance,metabolic syndrome, atherosclerosis, obesity, hyperlipidemia,hyperglycemia, high serum triglycerides, and/or high blood pressure.

In embodiments, the metabolic disorder is a diabetes associatedcomplication selected from nephropathy, retinopathy, neuropathy,cardiovascular disease, and inflammation. In embodiments, the metabolicdisorder is a diabetes associated disease selected from nephropathy,retinopathy, neuropathy, cardiovascular disease, and inflammation.

In embodiments, the method does not increase the risk for an infectiousdisease.

In embodiments, the method inhibits high glucose-induced TXNIP-TRXco-immunoprecipitation (e.g., in cell extracts or in vivo in cells). Inembodiments, the compound can bind to TXNIP and prevent its proteolysis.In embodiments, the method reduces expression of inflammatory cytokinemolecules in monocytes (e.g., TNF-α, IL-1β, IL-6, or chemokines).

In an aspect is provided a method of treating a kidney disease or an eyedisease, the method including administering to a subject in need thereofan effective amount of a compound, or pharmaceutically acceptable saltthereof, as described herein, including embodiments. In embodiments, thecompound has the formula:

W¹, W², L³, and R⁶ are as described herein, including in embodiments.

In an aspect is provided a method of reducing the level of expression ofTXNIP in a cell, the method including contacting the cell with acompound, or pharmaceutically acceptable salt thereof, as describedherein. In embodiments, the compound has the formula:

wherein W¹, W², L³, and R⁶ are as described herein, including inembodiments. In embodiments, the method includes reducing the level ofmRNA expression of TXNIP in a cell. In embodiments, the cell is aninflammatory white cell. In embodiments, the cell is a humaninflammatory cell. In embodiments, the cell is a mouse inflammatorycell. In embodiments, the cell is a pancreatic beta cell. Inembodiments, the pancreatic beta cell is a mouse pancreatic beta cell.In embodiments, the pancreatic beta cell is a human pancreatic betacell. In embodiments, the pancreatic beta cell is a primary human isletbeta cell. In embodiments, the cell is a THP1 cell. In embodiments, thecell is a human monocyte THP1 cell. In embodiments, the cell is amacrophage cell.

In embodiments, the level of expression of TXNIP is reduced by greaterthan 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or greater than 90% incomparison to a control in the absence of the compound. In embodiments,the level of expression of TXNIP is reduced by about 10%, 20%, 30%, 40%,50%, 60%, 70%, 80%, 90%, or about 100% in comparison to a control in theabsence of the compound. In embodiments, the level of expression ofTXNIP is reduced by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%in comparison to a control in the absence of the compound. Inembodiments, the level of expression of TXNIP is reduced by 1.5-fold,2-fold, 3-fold, 4-fold, 5-fold, 10-fold or lower than the expression oractivity in the absence of the compound.

In an aspect is provided a method of reducing the level of expression ofTNF-α in a cell, the method including contacting the cell with acompound, or pharmaceutically acceptable salt thereof, as describedherein. In embodiments, the compound has the formula:

wherein W¹, W², L³, and R⁶ are as described herein, including inembodiments. In embodiments, the method includes reducing the level ofmRNA expression of TNF-α in a cell. In embodiments, the cell is aninflammatory white cell. In embodiments, the cell is a humaninflammatory cell. In embodiments, the cell is a mouse inflammatorycell. In embodiments, the cell is a pancreatic beta cell. Inembodiments, the pancreatic beta cell is a mouse pancreatic beta cell.In embodiments, the pancreatic beta cell is a human pancreatic betacell. In embodiments, the pancreatic beta cell is a primary human isletbeta cell. In embodiments, the cell is a THP1 cell. In embodiments, thecell is a human monocyte THP1 cell. In embodiments, the cell is amacrophage cell.

In embodiments, the level of expression of TNF-α is reduced by greaterthan 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or greater than 90% incomparison to a control in the absence of the compound. In embodiments,the level of expression of TNF-α is reduced by about 10%, 20%, 30%, 40%,50%, 60%, 70%, 80%, 90%, or about 100% in comparison to a control in theabsence of the compound. In embodiments, the level of expression ofTNF-α is reduced by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%in comparison to a control in the absence of the compound. Inembodiments, the level of expression of TNF-α is reduced by 1.5-fold,2-fold, 3-fold, 4-fold, 5-fold, 10-fold or lower than the expression oractivity in the absence of the compound.

In an aspect is provided a method of reducing the level of expression ofTXNIP, the method including contacting TXNIP with a compound, or apharmaceutically acceptable salt thereof, as described herein. Inembodiments, the compound has the formula:

wherein W¹, W², L³, and R⁶ are as described herein, including inembodiments.

In embodiments, the level of expression of TXNIP is reduced by greaterthan 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or greater than 90% incomparison to a control in the absence of the compound. In embodiments,the level of expression of TXNIP is reduced by about 10%, 20%, 30%, 40%,50%, 60%, 70%, 80%, 90%, or about 100% in comparison to a control in theabsence of the compound. In embodiments, the level of expression ofTXNIP is reduced by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%in comparison to a control in the absence of the compound. Inembodiments, the level of expression of TXNIP is reduced by 1.5-fold,2-fold, 3-fold, 4-fold, 5-fold, 10-fold or lower than the expression oractivity in the absence of the compound.

In embodiments, the compound modulates (e.g., inhibits) the level ofexpression of FLNA. In embodiments, the compound modulates (e.g.,inhibits) the level of expression of MPEG1. In embodiments, the compoundmodulates (e.g., inhibits) the level of expression of TKTL1. Inembodiments, the compound modulates (e.g., inhibits) the level ofexpression of NATD1. In embodiments, the compound modulates (e.g.,inhibits) the level of expression of TXNIP. In embodiments, the compoundmodulates (e.g., inhibits) the level of expression of KLF10. Inembodiments, the compound modulates (e.g., inhibits) the level ofexpression of KLF2. In embodiments, the compound modulates (e.g.,inhibits) the level of expression of CD52. In embodiments, the compoundmodulates (e.g., inhibits) the level of expression of TNF. Inembodiments, the compound modulates (e.g., inhibits) the level ofexpression of ARRDC4. In embodiments, the compound modulates (e.g.,inhibits) the level of expression of JMJ1C-AS1. In embodiments, thecompound modulates (e.g., inhibits) the level of expression of RGMA. Inembodiments, the compound modulates (e.g., inhibits) the level ofexpression of EGR1. In embodiments, the compound modulates (e.g.,inhibits) the level of expression of NPIPA1. In embodiments, thecompound modulates (e.g., inhibits) the level of expression of G0S2. Inembodiments, the compound modulates (e.g., inhibits) the level ofexpression of EPHB1. In embodiments, the compound modulates (e.g.,inhibits) the level of expression of VSIG4. In embodiments, the compoundmodulates (e.g., inhibits) the level of expression of CFP. Inembodiments, the compound modulates (e.g., inhibits) the level ofexpression of CAPS. In embodiments, the compound modulates (e.g.,inhibits) the level of expression of GLUD1P3. In embodiments, thecompound modulates (e.g., inhibits) the level of expression of PCDHB14.In embodiments, the compound modulates (e.g., inhibits) the level ofexpression of CCDC153. In embodiments, the compound modulates (e.g.,inhibits) the level of expression of FAM229A. In embodiments, thecompound modulates (e.g., inhibits) the level of expression of SMURF2.In embodiments, the compound modulates (e.g., activates) the level ofexpression of PDE9A. In embodiments, the compound modulates (e.g.,activates) the level of expression of SLC44A2. In embodiments, thecompound modulates (e.g., activates) the level of expression ofARHGEF25. In embodiments, the compound modulates (e.g., activates) thelevel of expression of APBB1. In embodiments, the compound modulates(e.g., activates) the level of expression of GTF2IRD1. In embodiments,the compound modulates (e.g., activates) the level of expression ofLOC100506688. In embodiments, the compound modulates (e.g., activates)the level of expression of PPM1K. In embodiments, the compound modulates(e.g., activates) the level of expression of SLC16A2. In embodiments,the compound modulates (e.g., activates) the level of expression ofPCGF2. In embodiments, the compound modulates (e.g., activates) thelevel of expression of HK2. In embodiments, the compound modulates(e.g., activates) the level of expression of TSPAN2. In embodiments, thecompound modulates (e.g., activates) the level of expression of S1PR5.In embodiments, the compound modulates (e.g., activates) the level ofexpression of EFCAB7. In embodiments, the compound modulates (e.g.,activates) the level of expression of MACRODI. In embodiments, thecompound modulates (e.g., activates) the level of expression of GBP5. Inembodiments, the compound modulates (e.g., activates) the level ofexpression of KIAA1147. In embodiments, the compound modulates (e.g.,activates) the level of expression of ADGRE4P. In embodiments, thecompound modulates (e.g., activates) the level of expression of UQCRHL.In embodiments, the compound modulates (e.g., activates) the level ofexpression of DICER1-AS1. In embodiments, the compound modulates (e.g.,activates) the level of expression of PDIA3P1.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

V. Embodiments

Embodiment P1. A method of treating a TXNIP-TRX complex-associateddisease, said method comprising administering to a subject in needthereof an effective amount of a TXNIP-TRX complex inhibitor, whereinsaid TXNIP-TRX complex inhibitor has the formula:

whereinW¹ is —CR¹═, —N═, or —CH═;W² is —CR²═, —N═, or —CH═;R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —OCX¹ ₃, —OCH₂X¹,—OCHX¹ ₂, substituted or unsubstituted alkyl, or substituted orunsubstituted heteroalkyl;R² is independently halogen, —CX² ₃, —CHX² ₂, —CH₂X², —OCX² ₃, —OCH₂X²,—OCHX² ₂, substituted or unsubstituted alkyl, or substituted orunsubstituted heteroalkyl;L³ is a bond, —N(R³)—, —C(O)—, —C(O)N(R³)—, —N(R³)C(O)—, —N(H)—,—C(O)N(H)—, —N(H)C(O)—, —C(O)O—, substituted or unsubstituted alkylene,or substituted or unsubstituted heteroalkylene;R³ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl;R⁶ is independently hydrogen, halogen, —CX⁶ ₃, —CHX⁶ ₂, —CH₂X⁶, —OCX⁶ ₃,—OCH₂X⁶, —OCHX⁶ ₂, —CN, —SR^(6D), —SOR^(6D), —SO₂R^(6D), —SO₃R^(6D),—SO₄R^(6D), —SONR^(6A)R^(6B), —SO₂NR^(6A)R^(6B),—NR^(6C)C(O)NR^(6A)R^(6B), —N(O), —N(O)₂, —NR^(6A)R^(6B)—C(O)R^(6C),—C(O)—OR^(6C), —C(O)NR^(6A)R^(6B), —OR^(6D), —NR^(6A)SO₂R^(6D),—NR^(6A)C(O)R^(6C), —NR^(6A)C(O)OR^(6C), —NR^(6A)OR^(6C),—NR^(6C)NR^(6A)R^(6B), C(O)NR^(6C)NR^(6A)R^(6B) substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl; R^(6A), R^(6B), R^(6C), and R^(6D) are eachindependently hydrogen, oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl; andX¹, X², and X⁶ are independently —F, —Cl, —Br, or —I.

Embodiment P2. A method of treating a metabolic disorder, cardiovasculardisease, or inflammatory disease, said method comprising administeringto a subject in need thereof an effective amount of a compound, orpharmaceutically acceptable salt thereof, having the formula.

whereinW¹ is —CR¹═, —N═, or —CH═;W² is —CR²═, —N═, or —CH═;R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —OCX¹ ₃, —OCH₂X¹,—OCHX¹ ₂, substituted or unsubstituted alkyl, or substituted orunsubstituted heteroalkyl;R² is independently halogen, —CX² ₃, —CHX² ₂, —CH₂X², —OCX² ₃, —OCH₂X²,—OCHX² ₂, substituted or unsubstituted alkyl, or substituted orunsubstituted heteroalkyl;L³ is a bond, —N(R³)—, —C(O)—, —C(O)N(R³)—, —N(R³)C(O)—, —N(H)—,—C(O)N(H)—, —N(H)C(O)—, —C(O)O—, substituted or unsubstituted alkylene,or substituted or unsubstituted heteroalkylene;R³ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl;R⁶ is independently hydrogen, halogen, —CX⁶ ₃, —CHX⁶ ₂, —CH₂X⁶, —OCX⁶ ₃,—OCH₂X⁶, —OCHX⁶ ₂, —CN, —SR^(6D), —SOR^(6D), —SO₂R^(6D), —SO₃R^(6D),—SO₄R^(6D), —SONR^(6A)R^(6B), —SO₂NR^(6A)R^(6B),—NR^(6C)C(O)NR^(6A)R^(6B), —N(O), —N(O)₂, —NR^(6A)R^(6B)—C(O)R^(6C),—C(O)—OR^(6C), —C(O)NR^(6A)R^(6B), —OR^(6D), —NR^(6A)SO₂R^(6D),—NR^(6A)C(O)R^(6C), —NR^(6A)C(O)OR^(6C), —NR^(6A)OR^(6C),—NR^(6C)NR^(6A)R^(6B), —C(O)NR^(6C)NR^(6A)R^(6B), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl;R^(6A), R^(6B), R^(6C), and R^(6D) are each independently hydrogen, oxo,halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl,—CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂,—OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl; andX¹, X², and X⁶ are independently —F, —Cl, —Br, or —I.

Embodiment P3. The method of embodiment P1 or embodiment P2, wherein

R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —OCX¹ ₃, —OCH₂X¹,—OCHX¹ ₂, unsubstituted C₁-C₄ alkyl, or unsubstituted 2 to 4 memberedheteroalkyl;R² is independently halogen, —CX² ₃, —CHX² ₂, —CH₂X², —OCX² ₃, —OCH₂X²,—OCHX² ₂, unsubstituted C₁-C₄ alkyl, or unsubstituted 2 to 4 memberedheteroalkyl;L³ is a bond, —N(R³)—, —C(O)—, —C(O)N(R³)—, —N(R³)C(O)—, —N(H)—,—C(O)N(H)—, —N(H)C(O)—, —C(O)O—, R³-substituted or unsubstituted C₁-C₆alkylene, or R³-substituted or unsubstituted 2 to 6 memberedheteroalkylene;R³ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R⁴-substituted or unsubstitutedC₁-C₅ alkyl, R⁴-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R⁴-substituted or unsubstituted C₃-C₈ cycloalkyl,R⁴-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R⁴-substituted or unsubstituted C₆-C₁₀ aryl, or R⁴-substituted orunsubstituted 5 to 10 membered heteroaryl;R⁴ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R⁵-substituted or unsubstitutedC₁-C₈ alkyl, R⁵-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R⁵-substituted or unsubstituted C₃-C₈ cycloalkyl,R⁵-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R⁵-substituted or unsubstituted C₆-C₁₀ aryl, or R⁵-substituted orunsubstituted 5 to 10 membered heteroaryl;R⁵ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted C₁-C₈ alkyl,unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C₃-C₈cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl,unsubstituted C₆-C₁₀ aryl, or unsubstituted 5 to 10 membered heteroaryl;R⁶ is independently hydrogen, halogen, —CX⁶ ₃, —CHX⁶ ₂, —CH₂X⁶, —OCX⁶ ₃,—OCH₂X⁶, —OCHX⁶ ₂, —CN, —SR^(6D), —SOR^(6D), —SO₂R^(6D), —SO₃R^(6D),—SO₄R^(6D), —SONR^(6A)R^(6B), —SO₂NR^(6A)R^(6B),—NR^(6C)C(O)NR^(6A)R^(6B), —N(O), —N(O)₂, —NR^(6A)R^(6B)—C(O)R^(6C),—C(O)—OR^(6C), —C(O)NR^(6A)R^(6B), —OR^(6D), —NR^(6A)SO₂R^(6D),—NR^(6A)C(O)R^(6C), —NR^(6A)C(O)OR^(6C), —NR^(6A)OR^(6C),—NR^(6C)NR^(6A)R^(6B), —C(O)NR^(6C)NR^(6A)R^(6B), R⁷-substituted orunsubstituted C₁-C₈ alkyl, R⁷-substituted or unsubstituted 2 to 8membered heteroalkyl, R⁷-substituted or unsubstituted C₃-C₈ cycloalkyl,R⁷-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R⁷-substituted or unsubstituted C₆-C₁₀ aryl, or R⁷-substituted orunsubstituted 5 to 10 membered heteroaryl;R⁷ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R⁸-substituted or unsubstitutedC₁-C₈ alkyl, R⁸-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R⁸-substituted or unsubstituted C₃-C₈ cycloalkyl,R⁸-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R⁸-substituted or unsubstituted C₆-C₁₀ aryl, or R⁸-substituted orunsubstituted 5 to 10 membered heteroaryl;R⁸ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted C₁-C₈ alkyl,unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C₃-C₈cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl,unsubstituted C₆-C₁₀ aryl, or unsubstituted 5 to 10 membered heteroaryl;R^(6A) is independently hydrogen, oxo, halogen, —CCl₃, —CBr₃, —CF₃,—CI₃, CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(7A)-substituted or unsubstitutedC₁-C₈ alkyl, R^(7A)-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R^(7A)-substituted or unsubstituted C₃-C₈ cycloalkyl,R^(7A)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R^(7A)-substituted or unsubstituted C₆-C₁₀ aryl, or R^(7A)-substitutedor unsubstituted 5 to 10 membered heteroaryl;R^(7A) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(8A)-substituted or unsubstitutedC₁-C₈ alkyl, R^(8A)-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R^(8A)-substituted or unsubstituted C₃-C₈ cycloalkyl,R^(8A)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R^(8A)-substituted or unsubstituted C₆-C₁₀ aryl, or R^(8A)-substitutedor unsubstituted 5 to 10 membered heteroaryl;R^(8A) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted C₁-C₈ alkyl,unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C₃-C₈cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl,unsubstituted C₆-C₁₀ aryl, or unsubstituted 5 to 10 membered heteroaryl;R^(6B) is independently hydrogen, oxo, halogen, —CCl₃, —CBr₃, —CF₃,—CI₃, CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(7B)-substituted or unsubstitutedC₁-C₈ alkyl, R^(7B)-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R^(7B)-substituted or unsubstituted C₃-C₈ cycloalkyl,R^(7B)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R^(7B)-substituted or unsubstituted C₆-C₁₀ aryl, or R^(7B)-substitutedor unsubstituted 5 to 10 membered heteroaryl;R^(7B) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(8B)-substituted or unsubstitutedC₁-C₈ alkyl, R^(8B)-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R^(8B)-substituted or unsubstituted C₃-C₈ cycloalkyl,R^(8B)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R^(8B)-substituted or unsubstituted C₆-C₁₀ aryl, or R^(8B)-substitutedor unsubstituted 5 to 10 membered heteroaryl;R^(8B) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted C₁-C₈ alkyl,unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C₃-C₈cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl,unsubstituted C₆-C₁₀ aryl, or unsubstituted 5 to 10 membered heteroaryl;R^(6C) is independently hydrogen, oxo, halogen, —CCl₃, —CBr₃, —CF₃,—CI₃, CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(7C)-substituted or unsubstitutedC₁-C₈ alkyl, R^(7C)-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R^(7C)-substituted or unsubstituted C₃-C₈ cycloalkyl,R^(7C)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R^(7C)-substituted or unsubstituted C₆-C₁₀ aryl, or R^(7C)-substitutedor unsubstituted 5 to 10 membered heteroaryl;R^(7C) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, —NHR^(8C), R^(8C)-substituted orunsubstituted C₁-C₈ alkyl, R^(8C)-substituted or unsubstituted 2 to 8membered heteroalkyl, R^(8C)-substituted or unsubstituted C₃-C₈cycloalkyl, R^(8C)-substituted or unsubstituted 3 to 8 memberedheterocycloalkyl, R^(8C)-substituted or unsubstituted C₆-C₁₀ aryl, orR^(8C)-substituted or unsubstituted 5 to 10 membered heteroaryl;R^(8C) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(9C)-substituted or unsubstitutedC₁-C₈ alkyl, R^(9C)-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R^(9C)-substituted or unsubstituted C₃-C₈ cycloalkyl,R^(9C)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R^(9C)-substituted or unsubstituted C₆-C₁₀ aryl, or R^(9C)-substitutedor unsubstituted 5 to 10 membered heteroaryl;R^(9C) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted C₁-C₈ alkyl,unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C₃-C₈cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl,unsubstituted C₆-C₁₀ aryl, or unsubstituted 5 to 10 membered heteroaryl;R^(6D) is independently hydrogen, oxo, halogen, —CCl₃, —CBr₃, —CF₃,—CI₃, CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(7D)-substituted or unsubstitutedC₁-C₈ alkyl, R^(7D)-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R^(7D)-substituted or unsubstituted C₃-C₈ cycloalkyl,R^(7D)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R^(7D)-substituted or unsubstituted C₆-C₁₀ aryl, or R^(7D)-substitutedor unsubstituted 5 to 10 membered heteroaryl;R^(7D) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(8D)-substituted or unsubstitutedC₁-C₈ alkyl, R^(8D)-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R^(8D)-substituted or unsubstituted C₃-C₈ cycloalkyl,R^(8D)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R^(8D)-substituted or unsubstituted C₆-C₁₀ aryl, or R^(8D)-substitutedor unsubstituted 5 to 10 membered heteroaryl;R^(8D) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted C₁-C₈ alkyl,unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C₃-C₈cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl,unsubstituted C₆-C₁₀ aryl, or unsubstituted 5 to 10 membered heteroaryl;X¹, X², and X⁶ are independently —F, —Cl, —Br, or —I.

Embodiment P4. The method of any one of embodiments P1 to P3, wherein W¹is —N═.

Embodiment P5. The method of any one of embodiments P1 to P3, wherein W¹is —CH═.

Embodiment P6. The method of any one of embodiments P1 to P3, wherein W¹is —CR¹═.

Embodiment P7. The method of any one of embodiments P1 to P6, wherein R¹is halogen.

Embodiment P8. The method of any one of embodiments P1 to P6, wherein R¹is —Cl.

Embodiment P9. The method of one of embodiments P1 to P8, wherein W² is—N═.

Embodiment P10. The method of one of embodiments P1 to P8, wherein W² is—CH═.

Embodiment P11. The method of one of embodiments P1 to P8, wherein W² is—CR²═.

Embodiment P12. The method of one of embodiments P1 to P11, wherein R²is halogen.

Embodiment P13. The method of one of embodiments P1 to P11, wherein R²is —Cl.

Embodiment P14. The method of one of embodiments P1 to P13, wherein L³is —N(H)— or R³-substituted or unsubstituted C₁-C₆ alkylene.

Embodiment P15. The method of one of embodiments P1 to P13, wherein L³is —N(H)—.

Embodiment P16. The method of one of embodiments P1 to P13, wherein L³is R³-substituted or unsubstituted C₁-C₆ alkylene.

Embodiment P17. The method of one of embodiments P1 to P16, wherein R³is independently —COOH, —CONH₂, R⁴-substituted or unsubstituted C₁-C₄alkyl, R⁴-substituted or unsubstituted 2 to 4 membered heteroalkyl,R⁴-substituted or unsubstituted C₅-C₆ cycloalkyl, R⁴-substituted orunsubstituted 5 to 6 membered heterocycloalkyl, R⁴-substituted orunsubstituted C₆-C₁₀ aryl, or R⁴-substituted or unsubstituted 5 to 10membered heteroaryl.

Embodiment P18. The method of one of embodiments P1 to P16, wherein R³is independently —COOH.

Embodiment P19. The method of one of embodiments P1 to P16, wherein R³is independently R⁴-substituted or unsubstituted 2 to 4 memberedheteroalkyl.

Embodiment P20. The method of one of embodiments P1 to P16, wherein R³is independently —S(O)CH₃.

Embodiment P21. The method of one of embodiments P1 to P16, wherein R³is independently R⁴-substituted or unsubstituted C₆-C₁₀ aryl.

Embodiment P22. The method of embodiment P21, wherein R⁴ isindependently oxo or halogen.

Embodiment P23. The method of one of embodiments P1 to P16, wherein R³is independently unsubstituted phenyl.

Embodiment P24. The method of one of embodiments P1 to P16, wherein R³is independently

Embodiment P25. The method of one of embodiments P1 to P24, wherein R⁶is independently —SOR^(6D), —C(O)R^(6C), —C(O)—OR^(6C),—C(O)NR^(6A)R^(6B), —NR^(6A)C(O)R^(6C) or —C(O)NR^(6C)NR^(6A)R^(6B).

Embodiment P26. The method of one of embodiments P1 to P24, wherein R⁶is —SOR^(6D).

Embodiment P27. The method of embodiment P26, wherein R^(6D) isR^(7D)-substituted or unsubstituted C₁-C₄ alkyl.

Embodiment P28. The method of embodiment P26, wherein R^(6D) isunsubstituted methyl.

Embodiment P29. The method of one of embodiments P1 to P24, wherein R⁶is —C(O)R^(6C).

Embodiment P30. The method of embodiment P29, wherein R^(6C) isR^(7C)-substituted or unsubstituted 6 membered heterocycloalkyl.

Embodiment P31. The method of embodiment P29, wherein R^(6C) isR^(7C)-substituted piperazinyl, R^(7C)-substituted piperidinyl, orunsubstituted morpholinyl.

Embodiment P32. The method of embodiment P31, wherein R^(7C) is—NHR^(8C) or R^(8C)-substituted phenyl.

Embodiment P33. The method of embodiment P32, wherein R^(8C) isunsubstituted C₁-C₄ alkyl, unsubstituted 2 to 4 membered heteroalkyl,unsubstituted C₅-C₆ cycloalkyl, unsubstituted 5 to 6 memberedheterocycloalkyl, R^(9C)-substituted or unsubstituted phenyl, orunsubstituted 5 to 6 membered heteroaryl.

Embodiment P34. The method of embodiment P32, wherein R^(8C) isunsubstituted methoxy or R^(9C)-substituted phenyl; and R^(9C) isunsubstituted isopropyl.

Embodiment P35. The method of one of embodiments P1 to P24, wherein R⁶is —C(O)—OR^(6C).

Embodiment P36. The method of embodiment P35, wherein R^(6C) ishydrogen, R^(7C)-substituted or unsubstituted C₁-C₅ alkyl orR^(7C)-substituted or unsubstituted C₆-C₁₀ aryl.

Embodiment P37. The method of embodiment P35, wherein R^(6C) ishydrogen, R^(7C)-substituted or unsubstituted ethyl orR^(7C)-substituted or unsubstituted phenyl.

Embodiment P38. The method of embodiment P37, wherein R^(7C) is oxo,R^(8C)-substituted or unsubstituted C₁-C₂ alkyl, unsubstituted 2 to 3membered heteroalkyl, or R^(8C)-substituted or unsubstituted C₆-C₁₀aryl.

Embodiment P39. The method of embodiment P38, wherein R^(8C) is oxo,halogen, unsubstituted C₁-C₄ alkyl, or unsubstituted phenyl.

Embodiment P40. The method of embodiment P38, wherein R^(8C) is oxo,—Cl, —Br, unsubstituted methyl, or unsubstituted phenyl.

Embodiment P41. The method of embodiment P35, wherein R^(6C) ishydrogen.

Embodiment P42. The method of one of embodiments P1 to P24, wherein R⁶is —C(O)NR^(6A)R^(6B).

Embodiment P43. The method of embodiment P42, wherein R^(6A) ishydrogen.

Embodiment P44. The method of one of embodiments P42 to P43, whereinR^(6B) is R^(7B)-substituted or unsubstituted C₁-C₆ alkyl,R^(7B)-substituted or unsubstituted phenyl, or R^(7B)-substituted orunsubstituted 5 to 6 membered heteroaryl.

Embodiment P45. The method of one of embodiments P42 to P43, whereinR^(6B) is R^(7B)-substituted C₁-C₆ alkyl, R^(7B)-substituted phenyl, orR^(7B)-substituted pyridyl.

Embodiment P46. The method of one of embodiments P44 to P42, whereinR^(7B) is halogen, unsubstituted C₁-C₃ alkyl, R^(8B)-substituted orunsubstituted 2 to 4 membered heteroalkyl, or unsubstituted C₆-C₁₀ aryl.

Embodiment P47. The method of one of embodiments P41 to P45, whereinR^(7B) is —Cl, —Br, unsubstituted methyl, unsubstituted ethyl,unsubstituted isopropyl, unsubstituted methoxy, R^(8B)-substituted 3 to4 membered heteroalkyl, or unsubstituted phenyl.

Embodiment P48. The method of one of embodiments P46 to P47, whereinR^(8B) is oxo.

Embodiment P49. The method of one of embodiments P1 to P24, wherein R⁶is —NR^(6A)C(O)R^(6C).

Embodiment P50. The method of embodiment P49, wherein R^(6A) ishydrogen.

Embodiment P51. The method of one of embodiments P49 to P50, whereinR^(6C) is R^(7C)-substituted or unsubstituted C₆-C₁₀ aryl orunsubstituted 5 to 10 membered heteroaryl.

Embodiment P52. The method of one of embodiments P49 to P50, whereinR^(6C) is R^(7C)-substituted or unsubstituted phenyl or unsubstitutedpyridyl.

Embodiment P53. The method of one of embodiments P51 to P52, whereinR^(7C) is R^(8C)-substituted C₁-C₆ alkyl.

Embodiment P54. The method of embodiment P53, wherein R^(8C) is oxo.

Embodiment P55. The method of one of embodiments P1 to P24, wherein R⁶is —C(O)NR^(6C)NR^(6A)R^(6B).

Embodiment P56. The method of embodiment P55, wherein R^(6A) and R^(6C)are hydrogen.

Embodiment P57. The method of one of embodiments P55 to P56, whereinR^(6B) is R^(7B)-substituted C₁-C₆ alkyl.

Embodiment P58. The method of embodiment P57, wherein R^(7B) isindependently oxo, R^(8B)-substituted or unsubstituted C₆-C₁₀ aryl, orunsubstituted 5 to 10 membered heteroaryl.

Embodiment P59. The method of embodiment P57, wherein R^(7B) isindependently oxo, R^(8B)-substituted C₆-C₁₀ aryl, or unsubstitutedpyridyl.

Embodiment P60. The method of one of embodiments P58 to P59, whereinR^(8B) is oxo.

Embodiment P61. The method of embodiment P57, wherein R^(7B) isindependently oxo,

or unsubstituted pyridyl.

Embodiment P62. The method of one of embodiments P1 to P61, wherein thecompound is capable of inhibiting TXNIP protein activity or function,said method comprising contacting the TXNIP protein with the compound.

Embodiment P63. The method of one of embodiments P1 to P61, wherein thecompound is capable of inhibiting TXNIP protein binding to TRX, saidmethod comprising contacting the TXNIP protein with the compound.

Embodiment P64. The method of one of embodiments P1 to P61, wherein themetabolic disorder is diabetes.

Embodiment P65. The method of embodiment P64, wherein the diabetes isT1D.

Embodiment P66. The method of embodiment P64, wherein the diabetes isT2D.

Embodiment P67. The method of embodiment P64, wherein the diabetes isassociated with islet beta cell dysfunction.

Embodiment P68. The method of one of embodiments P1 to P61, wherein thecardiovascular disease is atherosclerosis.

Embodiment P69. The method of one of embodiments P1 to P61, wherein themetabolic disorder is a diabetes associated complication selected fromnephropathy, retinopathy, neuropathy, cardiovascular disease, andinflammation.

Embodiment P70. The method of one of embodiments P1 to P61, wherein themethod does not increase the risk for an infectious disease.

Embodiment P71. A pharmaceutical composition comprising a compound, orpharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient, wherein the compound has the formula:

whereinW¹ is —CR¹═, —N═, or —CH═;W² is —CR²═, —N═, or —CH═;R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —OCX¹ ₃, —OCH₂X¹,—OCHX¹ ₂, substituted or unsubstituted alkyl, or substituted orunsubstituted heteroalkyl;R² is independently halogen, —CX² ₃, —CHX² ₂, —CH₂X², —OCX² ₃, —OCH₂X²,—OCHX² ₂, substituted or unsubstituted alkyl, or substituted orunsubstituted heteroalkyl;L³ is a bond, —N(R³)—, —C(O)—, —C(O)N(R³)—, —N(R³)C(O)—, —N(H)—,—C(O)N(H)—, —N(H)C(O)—, —C(O)O—, substituted or unsubstituted alkylene,or substituted or unsubstituted heteroalkylene;R³ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl;R⁶ is independently hydrogen, halogen, —CX⁶ ₃, —CHX⁶ ₂, —CH₂X⁶, —OCX⁶ ₃,—OCH₂X⁶, —OCHX⁶ ₂, —CN, —SR^(6D), —SOR^(6D), —SO₂R^(6D), —SO₃R^(6D),—SO₄R^(6D), —SONR^(6A)R^(6B), —SO₂NR^(6A)R^(6B),—NR^(6C)C(O)NR^(6A)R^(6B), —N(O), —N(O)₂, —NR^(6A)R^(6B)—C(O)R^(6C),—C(O)—OR^(6C), —C(O)NR^(6A)R^(6B), —OR^(6D), —NR^(6A)SO₂R^(6D),—NR^(6A)C(O)R^(6C), —NR^(6A)C(O)OR^(6C), —NR^(6A)OR^(6C),—NR^(6C)NR^(6A)R^(6B), —C(O)NR^(6C)NR^(6A)R^(6B), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl;R^(6A), R^(6B), R^(6C), and R^(6D) are each independently hydrogen, oxo,halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl,—CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂,—OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl; andX¹, X², and X⁶ are independently —F, —Cl, —Br, or —I.

VI. Additional Embodiments

Embodiment 1. A method of treating a TXNIP-TRX complex-associateddisease, said method comprising administering to a subject in needthereof an effective amount of a TXNIP-TRX complex inhibitor, whereinsaid TXNIP-TRX complex inhibitor has the formula:

whereinW¹ is —CR¹═, —N═, or —CH═;W² is —CR²═, —N═, or —CH═;R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —OCX¹ ₃, —OCH₂X¹,—OCHX¹ ₂, substituted or unsubstituted alkyl, or substituted orunsubstituted heteroalkyl;R² is independently halogen, —CX² ₃, —CHX² ₂, —CH₂X², —OCX² ₃, —OCH₂X²,—OCHX² ₂, substituted or unsubstituted alkyl, or substituted orunsubstituted heteroalkyl;L³ is a bond, —N(R³)—, —C(O)—, —C(O)N(R³)—, —N(R³)C(O)—, —N(H)—,—C(O)N(H)—, —N(H)C(O)—, —C(O)O—, substituted or unsubstituted alkylene,or substituted or unsubstituted heteroalkylene;R³ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl;R⁶ is independently hydrogen, halogen, —CX⁶ ₃, —CHX⁶ ₂, —CH₂X⁶, —OCX⁶ ₃,—OCH₂X⁶, —OCHX⁶ ₂, —CN, —SR^(6D), —SOR^(6D), —SO₂R^(6D), —SO₃R^(6D),—SO₄R^(6D), —SONR^(6A)R^(6B)—SO₂NR^(6A)R^(6B),—NR^(6C)C(O)NR^(6A)R^(6B), —N(O), —N(O)₂, —NR^(6A)R^(6B)—C(O)R^(6C),—C(O)—OR^(6C), —C(O)NR^(6A)R^(6B), —OR^(6D), —NR^(6A)SO₂R^(6D),—NR^(6A)C(O)R^(6C), —NR^(6A)C(O)OR^(6C), —NR^(6A)OR^(6C),—NR^(6C)NR^(6A)R^(6B), —C(O)NR^(6C)NR^(6A)R^(6B), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl;R^(6A), R^(6B), R^(6C), and R^(6D) are each independently hydrogen, oxo,halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl,—CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂,—OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl; andX¹, X², and X⁶ are independently —F, —Cl, —Br, or —I.

Embodiment 2. A method of treating a metabolic disorder, cardiovasculardisease, or inflammatory disease, said method comprising administeringto a subject in need thereof an effective amount of a compound, orpharmaceutically acceptable salt thereof, having the formula.

whereinW¹ is —CR¹═, —N═, or —CH═;W² is —CR²═, —N═, or —CH═;R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —OCX¹ ₃, —OCH₂X¹,—OCHX¹ ₂, substituted or unsubstituted alkyl, or substituted orunsubstituted heteroalkyl;R² is independently halogen, —CX² ₃, —CHX² ₂, —CH₂X², —OCX² ₃, —OCH₂X²,—OCHX² ₂, substituted or unsubstituted alkyl, or substituted orunsubstituted heteroalkyl;L³ is a bond, —N(R³)—, —C(O)—, —C(O)N(R³)—, —N(R³)C(O)—, —N(H)—,—C(O)N(H)—, —N(H)C(O)—, —C(O)O—, substituted or unsubstituted alkylene,or substituted or unsubstituted heteroalkylene;R³ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl;R⁶ is independently hydrogen, halogen, —CX⁶ ₃, —CHX⁶ ₂, —CH₂X⁶, —OCX⁶ ₃,—OCH₂X⁶, —OCHX⁶ ₂, —CN, —SR^(6D), —SOR^(6D), —SO₂R^(6D), —SO₃R^(6D),—SO₄R^(6D), —SONR^(6A)R^(6B)—SO₂NR^(6A)R^(6B),—NR^(6C)C(O)NR^(6A)R^(6B), —N(O), —N(O)₂, —NR^(6A)R^(6B)—C(O)R^(6C),—C(O)—OR^(6C), —C(O)NR^(6A)R^(6B), —OR^(6D), —NR^(6A)SO₂R^(6D),—NR^(6A)C(O)R^(6C), —NR^(6A)C(O)OR^(6C), —NR^(6A)OR^(6C),—NR^(6C)NR^(6A)R^(6B), —C(O)NR^(6C)NR^(6A)R^(6B), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl;R^(6A), R^(6B), R^(6C), and R^(6D) are each independently hydrogen, oxo,halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl,—CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂,—OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl; andX¹, X², and X⁶ are independently —F, —Cl, —Br, or —I.

Embodiment 3. The method of embodiment 1 or embodiment 2, wherein

R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —OCX¹ ₃, —OCH₂X¹,—OCHX¹ ₂, unsubstituted C₁-C₄ alkyl, or unsubstituted 2 to 4 memberedheteroalkyl;R² is independently halogen, —CX² ₃, —CHX² ₂, —CH₂X², —OCX² ₃, —OCH₂X²,—OCHX² ₂, unsubstituted C₁-C₄ alkyl, or unsubstituted 2 to 4 memberedheteroalkyl;L³ is a bond, —N(R³)—, —C(O)—, —C(O)N(R³)—, —N(R³)C(O)—, —N(H)—,—C(O)N(H)—, —N(H)C(O)—, —C(O)O—, R³-substituted or unsubstituted C₁-C₆alkylene, or R³-substituted or unsubstituted 2 to 6 memberedheteroalkylene;R³ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R⁴-substituted or unsubstitutedC₁-C₈ alkyl, R⁴-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R⁴-substituted or unsubstituted C₃-C₈ cycloalkyl,R⁴-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R⁴-substituted or unsubstituted C₆-C₁₀ aryl, or R⁴-substituted orunsubstituted 5 to 10 membered heteroaryl;R⁴ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R⁵-substituted or unsubstitutedC₁-C₈ alkyl, R⁵-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R⁵-substituted or unsubstituted C₃-C₈ cycloalkyl,R⁵-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R⁵-substituted or unsubstituted C₆-C₁₀ aryl, or R⁵-substituted orunsubstituted 5 to 10 membered heteroaryl;R⁵ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted C₁-C₅ alkyl,unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C₃-C₈cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl,unsubstituted C₆-C₁₀ aryl, or unsubstituted 5 to 10 membered heteroaryl;R⁶ is independently hydrogen, halogen, —CX⁶ ₃, —CHX⁶ ₂, —CH₂X⁶, —OCX⁶ ₃,—OCH₂X⁶, —OCHX⁶ ₂, —CN, —SR^(6D), —SOR^(6D), —SO₂R^(6D), —SO₃R^(6D),—SO₄R^(6D), —SONR^(6A)R^(6B)—SO₂NR^(6A)R^(6B),—NR^(6C)C(O)NR^(6A)R^(6B), —N(O), —N(O)₂, —NR^(6A)R^(6B)—C(O)R^(6C),—C(O)—OR^(6C), —C(O)NR^(6A)R^(6B), —OR^(6D), —NR^(6A)SO₂R^(6D),—NR^(6A)C(O)R^(6C), —NR^(6A)C(O)OR^(6C), —NR^(6A)OR^(6C),—NR^(6C)NR^(6A)R^(6B), —C(O)NR^(6C)NR^(6A)R^(6B), R⁷-substituted orunsubstituted C₁-C₈ alkyl, R⁷-substituted or unsubstituted 2 to 8membered heteroalkyl, R⁷-substituted or unsubstituted C₃-C₈ cycloalkyl,R⁷-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R⁷-substituted or unsubstituted C₆-C₁₀ aryl, or R⁷-substituted orunsubstituted 5 to 10 membered heteroaryl;R⁷ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R⁸-substituted or unsubstitutedC₁-C₈ alkyl, R⁸-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R⁸-substituted or unsubstituted C₃-C₈ cycloalkyl,R⁸-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R⁸-substituted or unsubstituted C₆-C₁₀ aryl, or R⁸-substituted orunsubstituted 5 to 10 membered heteroaryl;R⁸ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted C₁-C₅ alkyl,unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C₃-C₈cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl,unsubstituted C₆-C₁₀ aryl, or unsubstituted 5 to 10 membered heteroaryl;R^(6A) is independently hydrogen, oxo, halogen, —CCl₃, —CBr₃, —CF₃,—CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(7A)-substituted or unsubstitutedC₁-C₈ alkyl, R^(7A)-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R^(7A)-substituted or unsubstituted C₃-C₈ cycloalkyl,R^(7A)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R^(7A)-substituted or unsubstituted C₆-C₁₀ aryl, or R^(7A)-substitutedor unsubstituted 5 to 10 membered heteroaryl;R^(7A) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(8A)-substituted or unsubstitutedC₁-C₈ alkyl, R^(8A)-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R^(8A)-substituted or unsubstituted C₃-C₈ cycloalkyl,R^(8A)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R^(8A)-substituted or unsubstituted C₆-C₁₀ aryl, or R^(8A)-substitutedor unsubstituted 5 to 10 membered heteroaryl;R^(8A) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted C₁-C₈ alkyl,unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C₃-C₈cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl,unsubstituted C₆-C₁₀ aryl, or unsubstituted 5 to 10 membered heteroaryl;R^(6B) is independently hydrogen, oxo, halogen, —CCl₃, —CBr₃, —CF₃,—CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(7B)-substituted or unsubstitutedC₁-C₈ alkyl, R^(7B)-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R^(7B)-substituted or unsubstituted C₃-C₈ cycloalkyl,R^(7B)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R^(7B)-substituted or unsubstituted C₆-C₁₀ aryl, or R^(7B)-substitutedor unsubstituted 5 to 10 membered heteroaryl;R^(7B) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(8B)-substituted or unsubstitutedC₁-C₈ alkyl, R^(8B)-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R^(8B)-substituted or unsubstituted C₃-C₈ cycloalkyl,R^(8B)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R^(8B)-substituted or unsubstituted C₆-C₁₀ aryl, or R^(8B)-substitutedor unsubstituted 5 to 10 membered heteroaryl;R^(8B) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted C₁-C₅ alkyl,unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C₃-C₈cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl,unsubstituted C₆-C₁₀ aryl, or unsubstituted 5 to 10 membered heteroaryl;R^(6C) is independently hydrogen, oxo, halogen, —CCl₃, —CBr₃, —CF₃,—CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(7C)-substituted or unsubstitutedC₁-C₈ alkyl, R^(7C)-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R^(7C)-substituted or unsubstituted C₃-C₈ cycloalkyl,R^(7C)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R^(7C)-substituted or unsubstituted C₆-C₁₀ aryl, or R^(7C)-substitutedor unsubstituted 5 to 10 membered heteroaryl;R^(7C) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, —NHR^(8C), R^(8C)-substituted orunsubstituted C₁-C₈ alkyl, R^(8C)-substituted or unsubstituted 2 to 8membered heteroalkyl, R^(8C)-substituted or unsubstituted C₃-C₈cycloalkyl, R^(8C)-substituted or unsubstituted 3 to 8 memberedheterocycloalkyl, R^(8C)-substituted or unsubstituted C₆-C₁₀ aryl, orR^(8C)-substituted or unsubstituted 5 to 10 membered heteroaryl;R^(8C) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂CI,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R′C-substituted or unsubstitutedC₁-C₈ alkyl, R^(9C)-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R^(9C)-substituted or unsubstituted C₃-C₈ cycloalkyl,R^(9C)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R^(9C)-substituted or unsubstituted C₆-C₁₀ aryl, or R^(9C)-substitutedor unsubstituted 5 to 10 membered heteroaryl;R^(9C) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted C₁-C₅ alkyl,unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C₃-C₈cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl,unsubstituted C₆-C₁₀ aryl, or unsubstituted 5 to 10 membered heteroaryl;R^(6D) is independently hydrogen, oxo, halogen, —CCl₃, —CBr₃, —CF₃,—CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(7D)-substituted or unsubstitutedC₁-C₈ alkyl, R^(7D)-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R^(7D)-substituted or unsubstituted C₃-C₈ cycloalkyl,R^(7D)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R^(7D)-substituted or unsubstituted C₆-C₁₀ aryl, or R^(7D)-substitutedor unsubstituted 5 to 10 membered heteroaryl;R^(7D) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(8D)-substituted or unsubstitutedC₁-C₈ alkyl, R^(8D)-substituted or unsubstituted 2 to 8 memberedheteroalkyl, R^(8D)-substituted or unsubstituted C₃-C₈ cycloalkyl,R^(8D)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl,R″D-substituted or unsubstituted C₆-C₁₀ aryl, or R″D-substituted orunsubstituted 5 to 10 membered heteroaryl;R^(8D) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted C₁-C₅ alkyl,unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C₃-C₈cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl,unsubstituted C₆-C₁₀ aryl, or unsubstituted 5 to 10 membered heteroaryl;X¹, X², and X⁶ are independently —F, —Cl, —Br, or —I.

Embodiment 4. The method of one of embodiments 1 to 3, wherein W¹ is—N═.

Embodiment 5. The method of one of embodiments 1 to 3, wherein W¹ is—CH═.

Embodiment 6. The method of one of embodiments 1 to 3, wherein W¹ is—CR¹═.

Embodiment 7. The method of one of embodiments 1 to 6, wherein R¹ ishalogen.

Embodiment 8. The method of one of embodiments 1 to 6, wherein R¹ is—Cl.

Embodiment 9. The method of one of embodiments 1 to 8, wherein W² is—N═.

Embodiment 10. The method of one of embodiments 1 to 8, wherein W² is—CH═.

Embodiment 11. The method of one of embodiments 1 to 8, wherein W² is—CR².

Embodiment 12. The method of one of embodiments 1 to 11, wherein R² ishalogen.

Embodiment 13. The method of one of embodiments 1 to 11, wherein R² is—Cl.

Embodiment 14. The method of one of embodiments 1 to 13, wherein L³ is—N(H)— or R³-substituted or unsubstituted C₁-C₆ alkylene.

Embodiment 15. The method of one of embodiments 1 to 13, wherein L³ is—N(H)—.

Embodiment 16. The method of one of embodiments 1 to 13, wherein L³ isR³-substituted or unsubstituted C₁-C₆ alkylene.

Embodiment 17. The method of one of embodiments 1 to 16, wherein R³ isindependently —COOH, —CONH₂, R⁴-substituted or unsubstituted C₁-C₄alkyl, R⁴-substituted or unsubstituted 2 to 4 membered heteroalkyl,R⁴-substituted or unsubstituted C₅-C₆ cycloalkyl, R⁴-substituted orunsubstituted 5 to 6 membered heterocycloalkyl, R⁴-substituted orunsubstituted C₆-C₁₀ aryl, or R⁴-substituted or unsubstituted 5 to 10membered heteroaryl.

Embodiment 18. The method of one of embodiments 1 to 16, wherein R³ isindependently —COOH.

Embodiment 19. The method of one of embodiments 1 to 16, wherein R³ isindependently R⁴-substituted or unsubstituted 2 to 4 memberedheteroalkyl.

Embodiment 20. The method of one of embodiments 1 to 16, wherein R³ isindependently —S(O)CH₃.

Embodiment 21. The method of one of embodiments 1 to 16, wherein R³ isindependently R⁴-substituted or unsubstituted C₆-C₁₀ aryl.

Embodiment 22. The method of embodiment 21, wherein R⁴ is independentlyoxo or halogen.

Embodiment 23. The method of one of embodiments 1 to 16, wherein R³ isindependently unsubstituted phenyl.

Embodiment 24. The method of one of embodiments 1 to 16, wherein R³ isindependently

Embodiment 25. The method of one of embodiments 1 to 24, wherein R⁶ isindependently —SOR^(6D), —C(O)R^(6C), —C(O)—OR^(6C), —C(O)NR^(6A)R^(6B),—NR^(6A)C(O)R^(6C) or —C(O)NR^(6C)NR^(6A)R^(6B).

Embodiment 26. The method of one of embodiments 1 to 24, wherein R⁶ is—SOR^(6D).

Embodiment 27. The method of embodiment 26, wherein R⁶⁰ isR′-substituted or unsubstituted C₁-C₄ alkyl.

Embodiment 28. The method of embodiment 26, wherein R^(6D) isunsubstituted methyl.

Embodiment 29. The method of one of embodiments 1 to 24, wherein R⁶ is—C(O)R^(6C).

Embodiment 30. The method of embodiment 29, wherein R^(6C) isR^(7C)-substituted or unsubstituted 6 membered heterocycloalkyl.

Embodiment 31. The method of embodiment 29, wherein R^(6C) isR^(7C)-substituted piperazinyl, R^(7C)-substituted piperidinyl, orunsubstituted morpholinyl.

Embodiment 32. The method of embodiment 31, wherein R^(7C) is —NHR^(8C)or R^(8C)-substituted phenyl.

Embodiment 33. The method of embodiment 32, wherein R^(8C) isunsubstituted C₁-C₄ alkyl, unsubstituted 2 to 4 membered heteroalkyl,unsubstituted C₅-C₆ cycloalkyl, unsubstituted 5 to 6 memberedheterocycloalkyl, R^(9C)-substituted or unsubstituted phenyl, orunsubstituted 5 to 6 membered heteroaryl.

Embodiment 34. The method of embodiment 32, wherein R^(8C) isunsubstituted methoxy or R^(9C)-substituted phenyl; and R^(9C) isunsubstituted isopropyl.

Embodiment 35. The method of one of embodiments 1 to 24, wherein R⁶ is—C(O)—OR^(6C).

Embodiment 36. The method of embodiment 35, wherein R^(6C) is hydrogen,R^(7C)-substituted or unsubstituted C₁-C₅ alkyl or R^(7C)-substituted orunsubstituted C₆-C₁₀ aryl.

Embodiment 37. The method of embodiment 35, wherein R^(6C) is hydrogen,R^(7C)-substituted or unsubstituted ethyl or R^(7C)-substituted orunsubstituted phenyl.

Embodiment 38. The method of embodiment 37, wherein R^(7C) is oxo,R^(8C)-substituted or unsubstituted C₁-C₂ alkyl, unsubstituted 2 to 3membered heteroalkyl, or R^(8C)-substituted or unsubstituted C₆-C₁₀aryl.

Embodiment 39. The method of embodiment 38, wherein R^(8C) is oxo,halogen, unsubstituted C₁-C₄ alkyl, or unsubstituted phenyl.

Embodiment 40. The method of embodiment 38, wherein R^(8C) is oxo, —Cl,—Br, unsubstituted methyl, or unsubstituted phenyl.

Embodiment 41. The method of embodiment 35, wherein R^(6C) is hydrogen.

Embodiment 42. The method of one of embodiments 1 to 24, wherein R⁶ is—C(O)NR^(6A)R^(6B).

Embodiment 43. The method of embodiment 42, wherein R^(6A) is hydrogen.

Embodiment 44. The method of one of embodiments 42 to 43, wherein R^(6B)is R^(7B)-substituted or unsubstituted C₁-C₆ alkyl, R^(7B)-substitutedor unsubstituted phenyl, or R^(7B)-substituted or unsubstituted 5 to 6membered heteroaryl.

Embodiment 45. The method of one of embodiments 42 to 43, wherein R^(6B)is R^(7B)-substituted C₁-C₆ alkyl, R^(7B)-substituted phenyl, orR^(7B)-substituted pyridyl.

Embodiment 46. The method of one of embodiments 44 to 45, wherein R^(7B)is halogen, unsubstituted C₁-C₃ alkyl, R^(8B)-substituted orunsubstituted 2 to 4 membered heteroalkyl, or unsubstituted C₆-C₁₀ aryl.

Embodiment 47. The method of one of embodiments 41 to 45, wherein R^(7B)is —Cl, —Br, unsubstituted methyl, unsubstituted ethyl, unsubstitutedisopropyl, unsubstituted methoxy, R^(8B)-substituted 3 to 4 memberedheteroalkyl, or unsubstituted phenyl.

Embodiment 48. The method of one of embodiments 46 to 47, wherein R^(8B)is oxo.

Embodiment 49. The method of one of embodiments 1 to 24, wherein R⁶ is—NR^(6A)C(O)R^(6C).

Embodiment 50. The method of embodiment 49, wherein R^(6A) is hydrogen.

Embodiment 51. The method of one of embodiments 49 to 50, wherein R^(6C)is R^(7C)-substituted or unsubstituted C₆-C₁₀ aryl or unsubstituted 5 to10 membered heteroaryl.

Embodiment 52. The method of one of embodiments 49 to 50, wherein R^(6C)is R^(7C)-substituted or unsubstituted phenyl or unsubstituted pyridyl.

Embodiment 53. The method of one of embodiments 51 to 52, wherein R^(7C)is R^(8C)-substituted C₁-C₆ alkyl.

Embodiment 54. The method of embodiment 53, wherein R^(8C) is oxo.

Embodiment 55. The method of one of embodiments 1 to 24, wherein R⁶ is—C(O)NR^(6C)NR^(6A)R^(6B).

Embodiment 56. The method of embodiment 55, wherein R^(6A) and R^(6C)are hydrogen.

Embodiment 57. The method of one of embodiments 55 to 56, wherein R^(6B)is R^(7B)-substituted C₁-C₆ alkyl.

Embodiment 58. The method of embodiment 57, wherein R^(7B) isindependently oxo, R^(8B)-substituted or unsubstituted C₆-C₁₀ aryl, orunsubstituted 5 to 10 membered heteroaryl.

Embodiment 59. The method of embodiment 57, wherein R^(7B) isindependently oxo, R^(8B)-substituted C₆-C₁₀ aryl, or unsubstitutedpyridyl.

Embodiment 60. The method of one of embodiments 58 to 59, wherein R^(8B)is oxo.

Embodiment 61. The method of embodiment 57, wherein R^(7B) isindependently oxo,

or unsubstituted pyridyl.

Embodiment 62. The method of one of embodiments 1 to 3, wherein thecompound is

Embodiment 63. The method of one of embodiments 1 to 3, wherein thecompound is

Embodiment 64. The method of one of embodiments 1 to 63, wherein thecompound is capable of inhibiting TXNIP protein activity or function,said method comprising contacting the TXNIP protein with the compound.

Embodiment 65. The method of one of embodiments 1 to 63, wherein thecompound is capable of inhibiting TXNIP protein binding to TRX, saidmethod comprising contacting the TXNIP protein with the compound.

Embodiment 66. The method of one of embodiments 1 to 63, wherein themetabolic disorder is diabetes.

Embodiment 67. The method of embodiment 66, wherein the diabetes is T1D.

Embodiment 68. The method of embodiment 66, wherein the diabetes is T2D.

Embodiment 69. The method of embodiment 66, wherein the diabetes isassociated with islet beta cell dysfunction.

Embodiment 70. The method of one of embodiments 1 to 63, wherein thecardiovascular disease is atherosclerosis.

Embodiment 71. The method of one of embodiments 1 to 63, wherein themetabolic disorder is a diabetes associated disease selected fromnephropathy, retinopathy, neuropathy, cardiovascular disease, andinflammation.

Embodiment 72. The method of one of embodiments 1 to 63, wherein themethod does not increase the risk for an infectious disease.

Embodiment 73. A pharmaceutical composition comprising a compound, orpharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient, wherein the compound has the formula:

whereinW¹ is —CR¹═, —N═, or —CH═;W² is —CR²═, —N═, or —CH═;R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —OCX¹ ₃, —OCH₂X¹,—OCHX¹ ₂, substituted or unsubstituted alkyl, or substituted orunsubstituted heteroalkyl;R² is independently halogen, —CX² ₃, —CHX² ₂, —CH₂X², —OCX² ₃, —OCH₂X²,—OCHX² ₂, substituted or unsubstituted alkyl, or substituted orunsubstituted heteroalkyl;L³ is a bond, —N(R³)—, —C(O)—, —C(O)N(R³)—, —N(R³)C(O)—, —N(H)—,—C(O)N(H)—, —N(H)C(O)—, —C(O)O—, substituted or unsubstituted alkylene,or substituted or unsubstituted heteroalkylene;R³ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂,—CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl;R⁶ is independently hydrogen, halogen, —CX⁶ ₃, —CHX⁶ ₂, —CH₂X⁶, —OCX⁶ ₃,—OCH₂X⁶, —OCHX⁶ ₂, —CN, —SR^(6D), —SOR^(6D), —SO₂R^(6D), —SO₃R^(6D),—SO₄R^(6D), —SONR^(6A)R^(6B)—SO₂NR^(6A)R^(6B),—NR^(6C)C(O)NR^(6A)R^(6B), —N(O), —N(O)₂, —NR^(6A)R^(6B)—C(O)R^(6C),—C(O)—OR^(6C), —C(O)NR^(6A)R^(6B), —OR^(6D), —NR^(6A)SO₂R^(6D),—NR^(6A)C(O)R^(6C), —NR^(6A)C(O)OR^(6C), —NR^(6A)OR^(6C),—NR^(6C)NR^(6A)R^(6B), —C(O)NR^(6C)NR^(6A)R^(6B), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl;R^(6A), R^(6B), R^(6C), and R^(6D) are each independently hydrogen, oxo,halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl,—CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂,—OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl; andX¹, X², and X⁶ are independently —F, —Cl, —Br, or —I.

Examples Example 1: Inhibitors of TXNIP Action to Target Oxidant Stress,Inflammation, Diabetes, its Complications and Metabolic Memory

The thioredoxin system, which includes thioredoxin (TRX), nicotinamideadenine dinucleotide phosphate (NADPH) and thioredoxin reductase(TXNRD1), is a major anti-oxidant system involved in the maintenance ofcellular physiology and survival. Dysregulation in this system has beenassociated with metabolic and cardiovascular disorders.Thioredoxin-interacting protein (TXNIP) was first identified as aninhibitor of the redox regulator thioredoxin (TRX), an antioxidant.TXNIP functions as an inhibitor of TRX, and pathological suppression ofTRX by TXNIP (which leads to oxidant stress) has been demonstrated indiabetes and cardiovascular diseases.

In cells, TXNIP expression is modulated by redox stress, glucose levels,hypoxia and inflammatory activators etc. and is highly sensitive toglucose. High glucose [HG] greatly increases TXNIP expression. TXNIPexpression is greatly increased in pancreatic beta cells and isassociated with beta cell dysfunction and diabetes development.Furthermore, increased TXNIP expression is associated with severaldiabetic complications, including diabetic retinopathy, diabeticnephropathy, diabetic neuropathy, and cardiovascular disease. Evidenceshows that clinically used therapeutic agents for diabetes includinginsulin, metformin, angiotensin converting enzyme inhibitors and calciumchannel blockers reduce TXNIP expression. Verapamil, a clinically usedcompound for hypertension was recently shown (Nature Med. 2018) toinhibit the expression of TXNIP and improve beta cell function insubjects with type 1 diabetes (Nat Med 2018). This provides strongevidence for the proof of concept that inhibition of TXNIP is clinicallyviable therapeutic strategy in treatment of T1D and T2D.

Recent studies from our laboratory (Zhen et al., PNAS 2016) havedemonstrated a novel connection between epigenetic modification (DNAmethylation) of TXNIP and Metabolic Memory, in which prior episodes ofhyperglycemia can lead to the continued development of diabeticcomplications in certain diabetic patients despite subsequent glucosecontrol: a major challenge in the clinical management of diabetes. Ourdata from that study, as well as our recent data from a much biggercohort, shows TXNIP is highly induced by HG and inflammatory cytokines,and TXNIP molecule depicts the most significant changes in epigeneticDNA methylation in patients with metabolic memory of diabeticcomplications. Notably, we found that this alteration in TXNIP DNAmethylation remained sustained in the same patient at two different timepoints 17 years apart (i.e. it depicts epigenetic memory). Furthermore,our data suggests that the known connections between HbA1c and diabeticcomplications can also be explained by epigenetic changes at TXNIP andother genomic loci.

A similar memory effect has also been documented in type 2 diabetes(T2D), referred as “legacy effect”. Interestingly, studies from othergroups have recently shown that a similar epigenetic modification ofTXNIP (as that noted by us) is also seen in patients with type 2diabetes, insulin resistance (obesity) and dyslipidemia.

Taken together the data from our lab show strong connections betweenTXNIP and its epigenetic modifications in inflammation, diabeticcomplications, metabolic memory and hyperglycemia. Data from others havealso shown its pathological role in beta cell function, in both T1D andT2D. Thus our objective is to identify small molecules that caninactivate TXNIP functions by directly binding/interacting with it in away that will disrupt its interaction with TRX. This approach isdifferent from how some of the known compounds that target theexpression of TXNIP. The TXNIP inhibitors available to date, target theexpression of TXNIP. Such a strategy could cause side effects sinceTXNIP has multiple functionalities in the cell. The strategy describedherein is to specifically downregulate TXNIP functions by targeting theTXNIP-TRX complex formation. The levels of the TXNIP-TRX complex areincreased under certain diseases (e.g., diabetic conditions). Such astrategy could reduce the number of adverse side effects caused duringtreatment. We believe that given the importance of epigeneticmodification of TXNIP, that targeting the interaction of TXNIP with TRXwould be a more effective therapeutic strategy.

Computational Screening of small molecule TXNTP inhibitors: To findsmall molecule inhibitors of TXNIP we collaborated with theComputational Therapeutics Core (CTC). The TXNIP-TRX protein-proteincomplex is a challenging target because TXNIP interacts with TRX througha covalent disulfide bond that requires more energy to break. Therefore,the direct interacting interface of the TXNIP-TRX complex is difficultto be targeted for small molecules. There is no known small moleculebinding site in TXNIP. This posed a challenge to identify and target anallosteric small molecule binding site to screen for candidatemolecules. An innovative computational method and software calledAllosteer to identify allosteric binding sites that are effective inallosteric inhibition (Bhattacharya 2014, 2016, Vaidehi 2016) was used.Using Allosteer we identified two putative binding sites as shown inFIG. 1A. We subsequently used a virtual ligand screening protocol d toscreen 263,000 small molecules from four small molecule databases in twoputative binding sites predicted using Allosteer. The virtual screeningof 263,000 compounds, generated a list of 40 compounds, which was thentrimmed to 26 for further experimental testing.

Experimental testing of small molecules: We developed three differentbench based assays to perform rigorous and reproducible tests for thepredicted hit molecules. These assays include testing direct binding toTXNIP as well as functional assays including under diabetic high glucoseconditions. The assays are: (1) drug affinity responsive targetstability test that tests the direct binding of the compounds. In thisassay, when a compound binds to its target molecule, it can reduce therate of its proteolytic digestion. (2) This assay looks for compoundsthat can interfere with the interaction between TXNIP and TRX in THP-1monocytes treated with high glucose. TXNIP is already highly expressedbecause the cells are treated with high glucose, and therefore wouldhave high concentration of TXNIP/TRX complexes in the cell extractCo-immunoprecipitation was done in these extracts through adding TRXantibody and the test compounds. If a compound can break the pre-formedTXNIP/TRX complex, there will be a reduced signal (band intensity) inthe assay. (3) The third assay is designed to test the effects ofcompounds on high glucose-induced effects in target cells.

Testing of 26 compounds were performed rigorously using the experimentalassays described above have led to the initial identification of aputative lead small molecule inhibitor of TXNIP, namely Compound C1,which can inhibit high glucose-induced TXNIP-TRX co-immunoprecipitationin cell extracts, in vivo in cells, can bind to TXNIP and prevent itsproteolysis, and also attenuate high glucose induced expression ofinflammatory cytokine molecules and TXNIP in monocytes.

The compound C1 (shown in FIG. 2A) works at micromolar concentrations.To find C1 analogs that work at nM concentrations, evaluation of analogsof C1 (FIG. 2B) that are predicted to have better affinity than C1 is inprogress.

Compound C1 and analogs with substitutions at various positions in theprimary template (e.g., shown in FIGS. 2A-2D) with similar or betteraffinity are being developed as effective drug candidates for a)preventing complications of diabetes (nephropathy, retinopathy,neuropathy, cardiovascular, inflammation; b) diabetes itself (reduceoxidative stress to protect against type 1 and type 2 diabetes caused byoxidant stress and inflammation induced islet beta cell dysfunction);and c) for patients depicting metabolic memory (blocking oxidant stress,may reduce the epigenetic modification of TXNIP).

Example 2. Computational Screening and Experimental Results

As indicated in Example 1, the data from our lab show strong connectionsbetween TXNIP and its epigenetic modifications in inflammation, diabeticcomplications, metabolic memory and hyperglycemia. Data from others havealso shown its pathological role in beta cell function, in both T1D andT2D. Thus our objective is to identify small molecules that caninactivate TXNIP functions by directly binding/interacting with it in away that will disrupt its interaction with TRX. This approach isdifferent from how some of the known compounds that target theexpression of TXNIP. We believe that given the importance of epigeneticmodification of TXNIP, that targeting the interaction of TXNIP with TRXwould be a more effective therapeutic strategy especially forcomplications and metabolic memory.

We therefore adopted a Computational modeling approach in collaborationwith our Computational Therapeutics Core (CTC) to screen candidatemolecules from large databases We then established a series ofexperimental assays to screen these candidates and identify leadcompounds. 40 hits were initially identified and 26 of these evaluatedby 3 different assays.

Computational Screening of small molecule TXNIP inhibitors: A virtualligand screening protocol was developed in Computational TherapeuticsCore at City of Hope, to screen 263,000 small molecules from four smallmolecule databases in two putative binding sites predicted usingAllosteer. After the virtual screening of 263,000 compounds, the CTCgave us a list of 40 compounds, which was then trimmed to 26 for furtherexperimental testing.

Experimental testing of small molecules: We developed three differentbench based assays to perform rigorous and reproducible tests for thepredicted hit molecules. These assays include testing direct binding toTXNIP as well as functional assays including under diabetic high glucoseconditions. The assays are: (1) drug affinity responsive targetstability test that tests the direct binding of the compounds. In thisassay, when a compound binds to its target molecule, it can reduce therate of its proteolytic digestion. (2) This assay looks for compoundsthat can interfere with the interaction between TXNIP and TRX in THP-1monocytes treated with high glucose. TXNIP is already highly expressedbecause the cells are treated with high glucose, and therefore wouldhave high concentration of TXNIP/TRX complexes in the cell extract.Co-immunopreciptation is done in these extracts through adding TRXantibody and the test compounds. If a compound can break the pre-formedTXNIP/TRX complex, there will be a reduced signal (band intensity) inthe assay. (3) The third assay is designed to test the effects ofcompounds on high glucose-induced effects in target cells.

Small molecules were screened generated using the computer modelingapproach shown below (done by the core). The first batch 26 compounds(selected from 40 based on availability) have been tested using 3different assays.

Assay 1: Co-immunoprecipitation (Co-IP) of TXNIP with TRX in THP 1monocytes cells treated with compounds under high glucose condition. Inthis assay, we looked for compounds that can interfere with theinteraction between TXNIP and TRX in THP-1 monocytes treated with HG. Sohere compounds are added to cells in culture. We found that in general,in this assay, the results are not very stable, and the false positiverate is high. However, the good part is that a positive control(metformin, a drug currently used to treat diabetes) works every time(ie it reduces the intensity of the band showing TXNIP-TRX binding incells treated with HG). So we picked the candidates only if the resultsare repeatable. FIGS. 4A-4B shows representative results: As seen inFIGS. 4A-4B, we observed that compound 1 (C1) reproducibly shows areduction in the HG-induced band.

Assay 2: Co-IP using extracts from THP 1 cells treated high glucose andin the presence of compounds. In this assay, TXNIP is already highlyexpressed (because the cells are treated with HG), we assume there ishigh concentration of TXNIP/TRX complexes in the cell extract. Co-IPswere done in these extracts through adding TRX antibody and compounds.If a compound is able to break the (pre-formed) TXNIP/TRX complex, therewill be a reduced signal (band intensity) in the assay.

In this type of assay, we see C1 reproducibly can affect TXNIP/TRXcomplex. Moreover, in this assay, Metformin (widely used drug fordiabetes) does not have any effect on TXNIP/TRX complex. This is becauseit is known that Metformin can reduce the expression of TXNIP throughthe AMPK pathway, and most likely not through interfering with theTXNIP/TRX complex.

Assay 3: DARTS Assay (drug affinity responsive target stability). Weadopted the DARTS assay because it is a straightforward method to checkif a compound interacts with TXNIP. In this assay, when a compound bindsto its target molecule, it can reduce the rate of its proteolyticdigestion. FIG. 6A shows that compound 1 (C1) is able to protect TXNIPfrom being proteolytically digested (20 min and 30 min panels, indicatedby arrows) at the concentration of 2 to 8 uM range. Further experimentsindicates that the protection can be seen with as low as 0.5 to 4 uM(FIG. 6B indicated by arrows).

Compound 1, ID 9264548 in ChemBridge EXP, appears promising as aTXNIP-TXR complex inhibitor. The compound has a molecular weight of 248and its chemical name is2-(1,3-dioxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-3-methylbutanoicacid.

Western blotting. Lysis buffer (25 mM Tris-HCl pH 7.5, 100 mM NaCl, 2.5mM EDTA and EGTA, 20 mM NaF, 1 mM Na3VO4, 20 mM Na b-glycerophosphate,10 mM Na pyrophosphate, 0.5% Triton X-100, 0.1% b-mercaptoethanol andprotease inhibitor cocktail [Roche]) was used to lyse the cells aftervarious treatments. SDS-PAGE-resolved proteins were transferred tonitrocellulose membrane. Antibodies used were rabbit anti-TXNIP (CellSignaling) and mouse anti-TRX (abcam ab16965).

RNA extraction and quantitative RT-PCR. RNA was extracted using theDirect-zol™ RNA MiniPrep Plus (Zymo Research). Reverse transcription ofRNA samples into cDNA was performed using GeneAmp RNA PCR Kit (AppliedBiosystems), dNTP (from Roche Applied Science), Rnase inhibitor, MULVReverse Transcriptase and Random hexamers reagent (all from Invitrogen).Diluted cDNA was quantified using real-time PCR performed with PowerSYBR Green qPCR MasterMix (Applied Biosystem) and 7500 real-time PCRsystem (Applied Biosystems). The HPRT1 gene was used as an internalcontrol.

Co-IP with compounds treated THP1 under high glucose condition. THP1cells were treated with compounds (2.5 uM) overnight and glucose was addto 25 mM and culture for 3-5 days, then coIP were carried using co-IPprotocol.

Co-IP with THP1 high glucose treated extract in the presence of thecompounds. THP1 cells were treated with 25 mM glucose for 3 days, thecell extract were prepared. Them 300 ul extract were used for TP.Compounds were added to 5 uM Co-IP were followed according to the Co-IPprotocol.

Co-IP Protocol

Harvest and Wash Cells

1. Transfer the cultured cells from the culture dish to a 15-mL conicaltube. 2.

Centrifuge at 500×g for 2 min at 4° C. and remove the supernatant. 3.Wash with ice-cold PBS and centrifuge at 500×g for 2 min at 4° C. Removethe supernatant. 4. Repeat Step 3 twice.

Cell Lysates Preparation

5. Resuspend the cell pellet in ice-cold cell lysis buffer (1 mL per1×10⁷ cells) and incubate on ice for 10 min. 6. Sonicate cells in icebath three times for 5 second pulses each. 7. Centrifuge at 13,000×g at4° C. for 10 min, and transfer the supernatant to a fresh tube. Storethe tube on ice for further use, or for long storage at −80° C.

Pre-Wash the Magnetic Beads

8. Resuspend the magnetic beads by pipetting up and down for severaltimes. 9. Transfer 20 μL of bead slurry to a fresh tube. Place the tubein a magnetic separation rack for seconds. Carefully remove thesupernatant once the solution is clear. 10. Add 200 μL of cell lysisbuffer (without protease inhibitor) to wash the magnetic bead pellet,pipette up and down for several seconds. Place the tube back in magneticseparation rack. Magnetize beads and remove the supernatant as dry aspossible. 11. Repeat Step 10 twice.

Pre-Clear the Lysate (Optional)

Note: Pre-clearing the lysate is recommended to reduce the non-specificbinding. However, if the protein is detected by western blotting,pre-clearing may not be necessary unless a contaminating protein isinterfering with visualization of the protein of interest. 12. Add 200 Lcell lysate to 20 μL of pre-washed magnetic beads. Note: The volume ofcell lysate depends on the expression level of the protein of interest.A starting concentration between 250 μg/mL-1.0 mg/mL is recommended. 13.Incubate for 20 min at room temperature with gentle agitation. 14.Pellet beads out from the lysate by a magnetic separation rack,carefully collect the pre-cleared cell lysate, and discard the magneticbead pellet.

Immunoprecipitation

15. Add relevant antibody to the pre-cleared cell lysate. Incubate for30 min at room temperature or overnight at 4° C. with gentle agitationto form the immunocomplex. 16. Pre-wash the magnetic beads as describedin Pre-wash the Magnetic Beads (Step 8 to Step 11). 17.

Transfer the lysate and antibody solution (immunocomplex) obtained inStep 15 to the tube containing the pre-washed magnetic bead pellet. 18.Incubate for 30 min at room temperature keeping gentle agitation. 19.Pellet beads using magnetic separation rack and discard the supernatant.20. Wash pellet with 500 uL cell lysis buffer (without proteaseinhibitor). Magnetize beads and remove the supernatant as dry aspossible. 21. Repeat Step 20 four times.

Elution

Note: There are three methods that can be used to elute the protein fromthe beads: SDS buffer elution, glycine buffer elution and urea bufferelution. Each of them have their own advantages. Here we describe anelution method based on SDS buffer, which is highly efficient. 22.Resuspend the pellet with 50 μL SDS buffer, pipette up and down forseveral times to mix the sample. 23. Boil the sample for 5 min. 24.Pellet beads using magnetic separation rack. Transfer the supernatant toa fresh tube for further analysis.

DARTS ASSAY. This assay was completed according to known methods in theart, namely: PNAS Dec. 22, 2009. 106 (51) 21984-21989; Methods Mol Biol.2015; 1263: 287-298.

Example 3: Screening TXNIP-Targeting Small Molecules in Murine and HumanCells

Thioredoxin interacting protein (TXNIP) is a glucose-response proteinand a major regulator of cellular redox signaling. It promotes oxidativestress in the pancreas and other organs, and is emerging as a keytherapeutic target in diabetes and its complications and metabolicmemory (Alhawiti et al., 2017; Chen et al., 2016; Chong et al., 2014;Shalev, 2014). Glucose induced overexpression of TXNIP results inincreased interaction with its partner thioredoxin, an antioxidant. Thisreduces the activity of thioredoxin and raises oxidative stress leadingto pancreatic beta cell death as well as dysfunction of several targetorgans (like kidneys, eyes, heart). Therefore, inhibiting TXNIPexpression and its interaction with thioredoxin (TRX) is a promisingtherapeutic route towards protecting islet beta cells againstdiabetes-induced attrition and diabetic complications. We report novelsmall molecule inhibitors of TXNIP that reduce TXNIP and TNF-αexpression in glucose-stimulated human monocytes and human pancreaticislet cells. Our evidence suggests these compounds disrupt theinteraction between TXNIP and its partner thioredoxin by binding toTXNIP. The compounds were discovered through screening of small moleculedatabases. The compounds may have therapeutic potential in type I andtype II diabetes.

Initial screening identified a leading TXNIP-targeting compound,referred to herein as C1. In support of the invention, data is presentedthat demonstrates the effects this compound upon TXNIP signaling in arange of cell types (inflammatory white cells and pancreatic beta cells)including THP1 cells (a human monocyte cell line), mouse RAW264.7macrophage cells, MIN6 mouse pancreas beta cells and 1.1 B4 humanpancreas beta cell line as well as primary human pancreatic islets. Eachcell type was treated with the lead compound and changes in TXNIP, TNF-α(as a marker of cell activation) quantified and other assays performed.Results obtained in cell experiments will inform in vivo animal studies.

C1 inhibited TXNIP mRNA expression in THP1 cells. FIG. 9A shows theeffects of concentration ranges of C1 on TXNIP mRNA expression in THP1human monocyte cell line. These results confirmed that C1 inhibit TXNIPexpression in a dose-dependent manner.

C1 treatment also reduced TNF-α expression in THP1 cells. FIG. 9B showsthe effects of treatment with the lead compound C1 on mRNA levels of theproinflammatory cytokine TNF-α. Treatment with this agent lead to lowerlevels of TNF-α mRNA, although this required higher concentrationscompared to those that suppressed TXNIP mRNA (FIG. 9A).

Treatment of murine RAW macrophages with C1 decreased TXNIP and TNF-α.It was not clear if C1 altered TXNIP and TNF-α mRNA levels in mousecells other than THP1 cells. To test this, we have tested the effects ofC1 in murine RAW macrophages. As in human THP1 cells, C1 inhibited TXNIPand TNF-α mRNA expression in mouse RAW cells (FIG. 10A and FIG. 10B).Thus, C1 alters mRNA levels in human and mouse inflammatory cells.

Treating murine MIN6 cells with C1 showed varying effects on key mRNAlevels. To ascertain the relevance of these effects upon pancreatic betacells, we tested C1 treatment on key target gene mRNA levels in murineMIN6 pancreatic beta cells. Interestingly, C1 decreased TXNIP (FIG. 11,left), but these murine MIN6 cells appeared to be less sensitive to C1.Also, C1 did not decrease TNF-α levels (FIG. 11, right panel). Thesedata are important in looking at the effects of C1 upon a range of cellstypes. They may also be of use in our in vivo mouse studies.

Treating human 1.1 B4 β cells with the lead compounds decreased TXNIPand TNF-α mRNA levels. We tested the effects of C1 in the human 1.1 B4pancreatic β cell line. The lead compound C1 strongly inhibited TXNIPmRNA expression (FIG. 12, left). Also, the compounds decreased TNF-αexpression (FIG. 12, right). Overall, human 1.1B4 ρ cells were found tobe sensitive to the lead compound. Together these data suggest thathuman cells are more sensitive to the effects of C1 compared to murinecells. This is relevant as C1 is being pursued for development for theclinic.

Discovery of lead compound analogues. A search of chemical libraries wasperformed in the interest of identifying possible analogues of leadcompound C1. Analogues to C1 were identified. They are named “A” batchcompounds (Table 1). To determine the properties of these C1 analogues,we treated THP1 cells with “A” batch compounds (5 uM) for three days,prepared RNA and measured TXNIP mRNA levels. None of the A batch C1analogues (except A31) displayed significant inhibitory effects on TXNIPmRNA expression in the assays employed (FIG. 13).

TXNIP interaction/binding with TRX is inhibited by C1. A primary goal ofthis research is to identify chemical compounds that block TXNIPinteractions with the target thioredoxin (TRX). To confirm such activityin our lead compound, we employed the well-established technique ofco-immunoprecipitation (co-IP). Our results indicated that basal TXNIPassociation/interaction with TRX (upper band, w. blot with TXNIPantibody) was significantly reduced at 48 h by treatment with C1 (FIG.14).

Treatment with C1 protects TXNIP from proteolysis. The drug affinityresponse target stability assay (DARTS assay) is a method to identifypotential protein targets (binders) of small molecules. The advantage ofthis method is being able to use the native small molecule withouthaving to immobilize or modify the protein (e.g., by incorporation ofbiotin, fluorescent molecules, radioisotope, or photo-affinity labels).In this case, it relies on the protection against proteolysis conferredon TXNIP by interaction with a small molecule (lead compound). FIG. 15shows that C1 protects TXNIP from proteolysis at 10 and 20 minutes(between 0.5 and 4 uM lanes).

To further confirm that C1 is able to protect TXNIP from proteolysis inthe presence of TXNIP+TRX1, we performed DARTS assay using pure TXNIPprotein (LSBio) and TRX1 protein (Sigma). The TRX1 protein we employedis also usually used for TRX1 activity assays. In contrast, the TXNIPprotein is generated by E. coli and might not be in the active form.Therefore, we re-natured the protein prior to use in the DARTS assay.FIG. 16 demonstrates that C1 protects purified TXNIP from proteolysis.

Treatment with C1 alters expression of a limited number of genesincluding TXNIP and TNFα. THP1 Cells were treated with or without C1under HG treated conditions, and gene differential analysis with RNA-seqwas performed and identified 20 up- and 24 down-regulated genes (FIG.17). We found that C1 treatment suppressed TXNIP and TNF-α, and thatoverall C1 alters the expression of only a limited number of genes.These data suggest that C1 may have less off-target effects with lowertoxicity. This is supported by preliminary cell toxicity study in THP1cells showing IC50 of 450 uM for C1.

Testing lead compounds in human pancreatic islets. To further explorethe effects of C1 as a possible therapy in diabetes, we conductedinitial translational studies in fresh primary human pancreatic islets.Results indicated C1 also efficiently inhibited TXNIP mRNA in isolatedhuman islets (FIG. 18). Further studies will explore a dose effect of C1upon these and other targets in human islets. We will also conductstudies to determine whether C1 can also improve islet functions.

TABLE 1 Structures of lead compounds and analogs.

C1

A1

A2

A4

A5

A6

A8

A9

A10

A11

A12

A13

A14

A15

A16

A17

A18

A19

A20

A21

A22

A23

A24

A25

A26

A27

A28

A29

A30

A31

A32

A33

Example 4: Materials and Methods

Computational protocol for identifying allosteric binding sites andsmall molecule inhibitors of TXNIP. Conventional high throughput virtualscreening methods have shown some success in identifying small moleculebinders for regular protein targets. However, these methods areinadequate for challenging targets such as TXNIP. TXNIP interacts withits partner TRX using covalent disulfide bonds, thereby making itimpossible to target the protein-protein interface using smallmolecules. While it is possible to identify small molecules that disruptthe interaction between TXNIP and TRX by binding to a distant site inTXNIP (allosteric site), such a problem is extremely challenging due to(A) difficulty of discovering novel druggable sites over the entireprotein surface, and (B) determining which of these sites will have thedesired inhibitory effect on TRX interaction upon drug binding. We haveaddressed these challenges by developing a combination of computationalin-silico methods and successfully applied them to TXNIP.

Our computational protocol for identifying small molecule inhibitors ofTXNIP may be divided into three steps: A) Identification of druggablebinding sites in TXNIP using the in-house program ‘FindBindSite’; B)Selection of suitable binding site(s) from (A) for inhibitor screeningusing the in-house program ‘Allosteer’; and C) Hierarchical screening ofsmall molecule databases in the selected sites in TXNIP, enhanced by anin-house filtering algorithm based on fragment pharmacophores, andselection of the final hits.

FindBindSite (FBS) is a method and software developed for identifyingsmall molecule binding sites in proteins (Li et al., 2014). FBS has beenvalidated against multiple protein targets (Li et al., 2014). As part ofthe FBS procedure, we first docked a database of 10,000 chemicallydiverse drug-like compounds to the entire protein surface of TXNIP. Thenwe clustered the docked compounds and analyzed the energetic andchemical properties of each cluster. The sites which docked the highestnumber of small molecules and showed the best overall binding energyscores were selected for further consideration. FIG. 3 shows the majordruggable sites in TXNIP (clusters) as identified by FBS.

Our next challenge was to determine which of the binding sites have thedesired inhibitory effect on TXNIP-TRX interaction. To this end, wecalculated the allosteric communication between the druggable sites andthe TRX interface using the in-house method Allosteer. The methodAllosteer and the associated software were developed, and have beenvalidated by applying to multiple protein targets including severalGPCRs and the phosphotyrosine phosphatase PTPN5 (Bhattacharya et al.,2016; Bhattacharya and Vaidehi, 2014; Nivedha et al., 2018; Tautermannet al., 2019; Vaidehi and Bhattacharya, 2016). Using extensive moleculardynamics simulations starting from the crystal structure of theTXNIP-TRX complex (Hwang et al., 2014), we calculated the allostericcommunication pipelines between the druggable sites and the TRXinterface. Two of the sites that showed the strongest allostericcommunication with the TRX interface were selected for drug design.Using Allosteer, we also identified the allosteric hotspots in eachbinding site (amino acid residues that play vital role in allostericmodulation of TRX binding), that would be critical in selecting thefinal hits. FIG. 3 shows the major allosteric pipelines as lines and thehotspot residues as sticks. The binding sites which were selected fordrug design are circled.

For drug screening, we used over 250,000 compounds from two smallmolecule databases from the vendors ZINC and ChemBridge Inc. Thescreening of small molecules to TXNIP was performed in three phasesusing the Glide software from Schrodinger (Friesner et al., 2004;Halgren et al., 2004). In the first phase, the small molecules weredocked to the two binding sites in TXNIP using the Glide StandardPrecision method (Friesner et al., 2004; Halgren et al., 2004). The top50,000 compounds from each site were selected by glide score and wereclustered by chemical similarity. The top 12,000 chemically diversecompounds were retained from this step and were subjected to bindingsite optimization using Prime and MacroModel from the Maestro Suite(Schrodinger™) (Bell et al., 2012), followed by binding free energycalculation. The top 600 compounds by binding free energy were retainedfrom each site. The final hits were selected based on low binding freeenergy, interaction with the allosteric hotspot residues, and manualvisualization of bound poses. A schematic of the screening process isshown in FIG. 19. Experimental testing of the top 40 hits obtained fromthis phase generated one lead compound, C1 (Table 1).

Next, the chemical structure of C1 was used to search the ChemBridgeonline database for analogous compounds. During the search, the centralaromatic moiety of C1, that makes major protein contacts, was retainedand substituents around this moiety were varied in the analogs. Intotal, 689 analogs were obtained which were then processed using Ligprepin Maestro (Bell et al., 2012) and the probable protonation states ofeach compound were determined. Then, MacroModel was used to generateunique conformations of each compound (Bell et al., 2012). In total,1637 conformations were generated for the 689 analogs. For the purposeof docking the C1 analogs, the TXNIP binding pocket was optimized inpresence of the compound C1 by reassigning side-chains within 5 Å of theligand, followed by minimization using PRIME/MMGBSA. The 1637 C1 analogconformations were then docked to the optimized TXNIP binding pocket andthe resulting docked poses were optimized through combined side chainreassignment and minimization of the binding pockets using Prime/MMGBSA,followed by binding free energy calculation. Next, compounds that werechemically the most distant from C1 were discarded. Then, the compoundsthat scored more than 10 kcal/mol lower binding energy than that of C1were further selected. These compounds were individually visualized andthe ones where the docked pose was very different than that of C1 wererejected. Finally, the resulting 92 compounds were clustered based onchemical fingerprint and the top compound (by binding free energy) fromeach cluster was selected for testing. This phase resulted in 33compounds (A1-A33, Table 1).

Western blotting. Cell extract buffer (Thermo Fisher Scientific) andprotease inhibitor cocktail [Roche]) were used to lyse cells aftervarious treatments. SDS-PAGE-resolved proteins were transferred tonitrocellulose membrane. Antibodies used were rabbit anti-TXNIP (CellSignaling) and mouse anti-TRX (Abcam ab16965).

RNA extraction and quantitative RT-PCR. RNA was extracted using theDirect-zol™ RNA MiniPrep Plus (Zymo Research). Reverse transcription ofRNA samples into cDNA was performed using the GeneAmp RNA PCR Kit(Applied Biosystems), dNTP (from Roche Applied Science), Rnaseinhibitor, MULV Reverse Transcriptase and Random hexamers reagent (allfrom Invitrogen). Diluted cDNA was quantified using real-time PCRperformed with Power SYBR Green qPCR MasterMix (Applied Biosystem) and7500 real-time PCR system (Applied Biosystems). The HPRT1 gene was usedas an internal control.

Co-immunoprecipitation. THP1 cells were treated with compounds (up to 10uM) overnight and glucose was added to 25 mM and cells cultured at 37°C. for 3-5 days. Co-IP with mouse anti-TRX antibody was performed usingstandard co-IP protocols. Rabbit anti-TXNIP antibody (Cell Signaling)was used for Western blotting.

Drug affinity responsive target stability (DARTS) assay. DARTS assay wasconducted according to a published protocol (Lomenick et al., 2009; Paiet al., 2015). THP1 cells were lysed with extract buffer. Lysates wereincubated on ice for 10 minutes and then centrifuged at 18,000 g for 10minutes at 4° C. and the pellet discarded. After mixing with variousamounts of pronase (Roche), lysate-pronase mixtures were incubated atroom temperature for 5-30 minutes, and SDS loading buffer added and themixture heated at 950° C. for 2 minutes. 10 μg of protein lysate wasapplied to SDS-polyacrylamide gels for electrophoresis and Westernblotting.

RNA-seq: Sequence alignment and gene counts. RNA-Seq reads were trimmedto remove sequencing adapters using Trimmomatic (Bolger et al., 2014),and polyA tails using FASTP (Chen et al., 2018). The processed readswere mapped to the human genome (hg19) using STAR software (v. 020201)(Dobin et al., 2013). The HTSeq software (v.0.6.0) (Anders and Huber,2010) was applied to generate the count matrix, with default parameters.

Differential gene expression analyses by RNA-seq. THP1 cells weretreated with High glucose (25 mM, 72 hr) with or without C1 addition,and then gene expression analysis was performed by RNA-sequencing.Differential expression analysis was conducted by adjusting read countsto normalized expression values using the TMM normalization method inedgeR package (Robinson et al., 2010). Prior to the alignment againstthe human genome (hg19) using STAR (Dobin et al., 2013), Trimmomatic(Bolger et al., 2014) was used to remove Illumina Sequencing adapters,while FASTP (Chen et al., 2018) was used to remove poly-A tails. Next,Raw counts for each gene in the GENCODE coding gene annotation (hg19)were measured using HTseq (Anders and Huber, 2010) with an argument of“-r pos -s reserve”. Differential expression was calculated using thesecounts with edgeR (5, 6) version 3.0. After correcting for differencesin library sizes, a fold change of >1.5 and a p-value of <0.05 wereapplied to select expressed genes. The corrected measures of the latterwere further processed using Cluster3.0 to generate a heatmap using JavaTreeView.

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1. (canceled)
 2. A method of treating a kidney disease, said method comprising administering to a subject in need thereof an effective amount of a compound, or pharmaceutically acceptable salt thereof, having the formula:

wherein W¹ is —CR¹═, —N═, or —CH═; W² is —CR²═, —N═, or —CH═; R¹ is halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —OCX¹ ₃, —OCH₂X¹, —OCHX¹ ₂, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R² is independently-halogen, —CX² ₃, —CHX² ₂, —CH₂X², —OCX² ₃, —OCH₂X², —OCHX² ₂, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; L³ is a bond, —N(R³)—, —C(O)—, —C(O)N(R³)—, —N(R³)C(O)—, —N(H)—, —C(O)N(H)—, —N(H)C(O)—, —C(O)O—, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; R³ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R⁶ is hydrogen, halogen, —CX⁶ ₃, —CHX⁶ ₂, —CH₂X⁶, —OCX⁶ ₃, —OCH₂X⁶, —OCHX⁶ ₂, —CN, —SR^(6D), —SOR^(6D), —SO₂R^(6D), —SO₃R^(6D), —SO₄R^(6D), —SONR^(6A)R^(6B)—SO₂NR^(6A)R^(6B), —NR^(6C)C(O)NR^(6A)R^(6B), —N(O), —N(O)₂, —NR^(6A)R^(6B), —C(O)R^(6C), —C(O)—OR^(6C), —C(O)NR^(6A)R^(6B), —OR^(6D), —NR^(6A)SO₂R^(6D), —NR^(6A)C(O)R^(6C), —NR^(6A)C(O)OR^(6C), —NR^(6A)OR^(6C), —NR^(6C)NR^(6A)R^(6B), —C(O)NR^(6C)NR^(6A)R^(6B), substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R^(6A), R^(6B), R^(6C) and R^(6D) are each independently hydrogen, oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; and X¹, X², and X⁶ are independently —F, —Cl, —Br, or —I.
 3. The method of claim 2, wherein R¹ is halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X₁, —OCX¹ ₃, —OCH₂X₁, —OCHX¹ ₂, unsubstituted C₁-C₄ alkyl, or unsubstituted 2 to 4 membered heteroalkyl; R² is halogen, —CX² ₃, —CHX² ₂, —CH₂X², —OCX² ₃, —OCH₂X², —OCHX² ₂, unsubstituted C₁-C₄ alkyl, or unsubstituted 2 to 4 membered heteroalkyl; L³ is a bond, —N(R³)—, —C(O)—, —C(O)N(R³)—, —N(R³)C(O)—, —N(H)—, —C(O)N(H)—, —N(H)C(O)—, —C(O)O—, R³-substituted or unsubstituted C₁-C₆ alkylene, or R³-substituted or unsubstituted 2 to 6 membered heteroalkylene; R³ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R⁴-substituted or unsubstituted C₁-C₈ alkyl, R⁴-substituted or unsubstituted 2 to 8 membered heteroalkyl, R⁴-substituted or unsubstituted C₃-C₈ cycloalkyl, R⁴-substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R⁴-substituted or unsubstituted C₆-C₁₀ aryl, or R⁴-substituted or unsubstituted 5 to 10 membered heteroaryl; R⁴ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R⁵-substituted or unsubstituted C₁-C₈ alkyl, R⁵-substituted or unsubstituted 2 to 8 membered heteroalkyl, R⁵-substituted or unsubstituted C₃-C₈ cycloalkyl, R⁵-substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R⁵-substituted or unsubstituted C₆-C₁₀ aryl, or R⁵-substituted or unsubstituted 5 to 10 membered heteroaryl; R⁵ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted C₁-C₅ alkyl, unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C₃-C₈ cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl, unsubstituted C₆-C₁₀ aryl, or unsubstituted 5 to 10 membered heteroaryl; R⁶ is hydrogen, halogen, —CX⁶ ₃, —CHX⁶ ₂, —CH₂X⁶, —OCX⁶ ₃, —OCH₂X⁶, —OCHX⁶ ₂, —CN, —SR^(6D), —SOR^(6D), —SO₂R^(6D), —SO₃R^(6D), —SO₄R^(6D), —SONR^(6A)R^(6B), —SO₂NR^(6A)R^(6B), —NR^(6C)C(O)NR^(6A)R^(6B), —N(O), —N(O)₂, —NR^(6A)R^(6B), —C(O)R^(6C), —C(O)—OR^(6C), —C(O)NR^(6A)R^(6B), —OR^(6D), —NR^(6A)SO₂R^(6D), —NR^(6A)C(O)R^(6C), —NR^(6A)C(O)OR^(6C), —NR^(6A)OR^(6C), —NR^(6C)NR^(6A)R^(6B), —C(O)NR^(6C)NR^(6A)R^(6B), R⁷-substituted or unsubstituted C₁-C₈ alkyl, R⁷-substituted or unsubstituted 2 to 8 membered heteroalkyl, R⁷-substituted or unsubstituted C₃-C₈ cycloalkyl, R⁷-substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R⁷-substituted or unsubstituted C₆-C₁₀ aryl, or R⁷-substituted or unsubstituted 5 to 10 membered heteroaryl; R⁷ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R⁸-substituted or unsubstituted C₁-C₈ alkyl, R⁸-substituted or unsubstituted 2 to 8 membered heteroalkyl, R⁸-substituted or unsubstituted C₃-C₈ cycloalkyl, R⁸-substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R⁸-substituted or unsubstituted C₆-C₁₀ aryl, or R⁸-substituted or unsubstituted 5 to 10 membered heteroaryl; R⁸ is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted C₁-C₅ alkyl, unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C₃-C₈ cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl, unsubstituted C₆-C₁₀ aryl, or unsubstituted 5 to 10 membered heteroaryl; R^(6A) is hydrogen, oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(7A)-substituted or unsubstituted C₁-C₈ alkyl, R^(7A)-substituted or unsubstituted 2 to 8 membered heteroalkyl, R^(7A) substituted or unsubstituted C₃-C₈ cycloalkyl, R^(7A)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R^(7A)-substituted or unsubstituted C₆-C₁₀ aryl, or R^(7A)-substituted or unsubstituted 5 to 10 membered heteroaryl; R^(7A) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(8A)-substituted or unsubstituted C₁-C₈ alkyl, R^(8A)-substituted or unsubstituted 2 to 8 membered heteroalkyl, R^(8A)-substituted or unsubstituted C₃-C₈ cycloalkyl, R^(8A)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R^(8A)-substituted or unsubstituted C₆-C₁₀ aryl, or R^(8A)-substituted or unsubstituted 5 to 10 membered heteroaryl; R^(8A) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted C₁-C₈ alkyl, unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C₃-C₈ cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl, unsubstituted C₆-C₁₀ aryl, or unsubstituted 5 to 10 membered heteroaryl; R^(6B) is hydrogen, oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(7B)-substituted or unsubstituted C₁-C₈ alkyl, R^(7B)-substituted or unsubstituted 2 to 8 membered heteroalkyl, R^(7B)-substituted or unsubstituted C₃-C₈ cycloalkyl, R^(7B)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R^(7B)-substituted or unsubstituted C₆-C₁₀ aryl, or R^(7B)-substituted or unsubstituted 5 to 10 membered heteroaryl; R^(7B) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(8B)-substituted or unsubstituted C₁-C₈ alkyl, R^(8B)-substituted or unsubstituted 2 to 8 membered heteroalkyl, R^(8B)-substituted or unsubstituted C₃-C₈ cycloalkyl, R^(8B)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R^(8B)-substituted or unsubstituted C₆-C₁₀ aryl, or R^(8B)-substituted or unsubstituted 5 to 10 membered heteroaryl; R^(8B) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted C₁-C₈ alkyl, unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C₃-C₈ cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl, unsubstituted C₆-C₁₀ aryl, or unsubstituted 5 to 10 membered heteroaryl; R^(6C) is hydrogen, oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(7C)-substituted or unsubstituted C₁-C₈ alkyl, R^(7C)-substituted or unsubstituted 2 to 8 membered heteroalkyl, R^(7C)-substituted or unsubstituted C₃-C₈ cycloalkyl, R^(7C)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R^(7C)-substituted or unsubstituted C₆-C₁₀ aryl, or R^(7C)-substituted or unsubstituted 5 to 10 membered heteroaryl; R^(7C) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, —NHR^(8C), R^(8C)-substituted or unsubstituted C₁-C₈ alkyl, R^(8C)-substituted or unsubstituted 2 to 8 membered heteroalkyl, R^(8C)-substituted or unsubstituted C₃-C₈ cycloalkyl, R^(8C)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R^(8C)-substituted or unsubstituted C₆-C₁₀ aryl, or R^(8C)-substituted or unsubstituted 5 to 10 membered heteroaryl; R^(8C) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(9C)-substituted or unsubstituted C₁-C₈ alkyl, R^(9C)-substituted or unsubstituted 2 to 8 membered heteroalkyl, R^(9C)-substituted or unsubstituted C₃-C₈ cycloalkyl, R^(9C)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R^(9C)-substituted or unsubstituted C₆-C₁₀ aryl, or R^(9C)-substituted or unsubstituted 5 to 10 membered heteroaryl; R^(9C) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted C₁-C₈ alkyl, unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C₃-C₈ cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl, unsubstituted C₆-C₁₀ aryl, or unsubstituted 5 to 10 membered heteroaryl; R^(6D) is -hydrogen, oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(7D)-substituted or unsubstituted C₁-C₈ alkyl, R^(7D)-substituted or unsubstituted 2 to 8 membered heteroalkyl, R^(7D)-substituted or unsubstituted C₃-C₈ cycloalkyl, R^(7D)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R^(7D)-substituted or unsubstituted C₆-C₁₀ aryl, or R^(7D)-substituted or unsubstituted 5 to 10 membered heteroaryl; R^(7D) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R^(8D)-substituted or unsubstituted C₁-C₈ alkyl, R^(8D)-substituted or unsubstituted 2 to 8 membered heteroalkyl, R^(8D)-substituted or unsubstituted C₃-C₈ cycloalkyl, R^(8D)-substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R^(8D)-substituted or unsubstituted C₆-C₁₀ aryl, or R^(8D)-substituted or unsubstituted 5 to 10 membered heteroaryl; R^(8D) is independently oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, unsubstituted C₁-C₈ alkyl, unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C₃-C₈ cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl, unsubstituted C₆-C₁₀ aryl, or unsubstituted 5 to 10 membered heteroaryl; and X¹, X², and X⁶ are independently —F, —Cl, —Br, or —I.
 4. The method of claim 2, wherein W¹ is —N═.
 5. The method of claim 2, wherein R¹ is —Cl.
 6. The method of claim 2, wherein W² is —CH═.
 7. The method of claim 2, wherein R² is —Cl.
 8. The method of claim 2, wherein L³ is —N(H)— or R³-substituted or unsubstituted C₁-C₆ alkylene.
 9. The method of claim 3, wherein R³ is independently —COOH, —CONH₂, R⁴-substituted or unsubstituted C₁-C₄ alkyl, R⁴-substituted or unsubstituted 2 to 4 membered heteroalkyl, R⁴-substituted or unsubstituted C₅-C₆ cycloalkyl, R⁴-substituted or unsubstituted 5 to 6 membered heterocycloalkyl, R⁴-substituted or unsubstituted C₆-C₁₀ aryl, or R⁴-substituted or unsubstituted 5 to 10 membered heteroaryl.
 10. The method of claim 2, wherein R⁶ is —SOR^(6D), —C(O)R^(6C), —C(O)—OR^(6C), —C(O)NR^(6A)R^(6B), —NR^(6A)C(O)R^(6C), or —C(O)NR^(6C)NR^(6A)R^(6B).
 11. The method of claim 3, wherein R⁶ is —C(O)—OR^(6C); and R^(6C) is hydrogen, R^(7C)-substituted or unsubstituted C₁-C₈ alkyl, or R^(7C)-substituted or unsubstituted C₆-C₁₀ aryl.
 12. The method of claim 2, wherein R⁶ is —C(O)NR^(6A)R^(6B).
 13. The method of claim 12, wherein R^(6A) is hydrogen.
 14. The method of claim 3, wherein R⁶ is —C(O)NR^(6A)R^(6B), and R^(6B) is R^(7B)-substituted or unsubstituted C₁-C₆ alkyl, R^(7B)-substituted or unsubstituted phenyl, or R^(7B)-substituted or unsubstituted 5 to 6 membered heteroaryl.
 15. The method of claim 2, wherein the compound is


16. The method of claim 2, wherein the compound is capable of inhibiting TXNIP protein activity or function.
 17. The method of claim 2, wherein the compound is capable of inhibiting TXNIP protein binding to TRX.
 18. The method of claim 2, wherein the kidney disease is nephropathy.
 19. The method of claim 2, wherein the kidney disease is diabetic nephropathy.
 20. (canceled) 